Lipid Inflammatory Mediators in Diabetic Vascular Disease
http://www.100md.com
《动脉硬化血栓血管生物学》
From the Gonda Diabetes Research Center (R.N.), Beckman Research Institute of City of Hope, Duarte Calif; and the Diabetes and Hormone Center of Excellence (J.L.N.), University of Virginia School of Medicine, Charlottesville, Va.
Series Editor: Richard A. Cohen
ATVB in Focus
Diabetic Vascular Disease: Pathophysiological Mechanisms in the Diabetic
Milieu and Therapeutic Implications
Previous Brief Review in this Series:
?Naka Y, Bucciarelli LG, Wendt T, Lee LK, Rong LL, Ramasamy R, Yan SF, Schmidt AM. RAGE axis: animal models and novel insights into the vascular complications of diabetes. 2004;24:1342–1349.
ABSTRACT
Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease.
Evidence suggests that inflammatory responses in the vasculature can be elicited by small oxidized lipids that are components of oxidized low-density lipoprotein or products of the lipoxygenase and cyclooxygenase pathways of arachidonic and linoleic acid metabolism. This review evaluates these inflammatory and proatherogenic pathways in the pathogenesis of diabetic vascular disease.
Key Words: lipoxygenase ? diabetes ? diabetes complications ? inflammation ? lipids
Introduction
Diabetes is associated with significantly accelerated rates of cardiovascular complications such as atherosclerosis and hypertension. In particular, type 2 diabetes is associated with 2- to 4-fold increase in coronary artery disease.1 This has been attributed to the clustering of several risk factors, including insulin resistance, hypertension, obesity, and dyslipidemia.2,3 Multiple mechanisms contribute to vascular and arterial disease in the diabetic population.2 Basic biochemical mechanisms have been described by which hyperglycemia-induced oxidant stress activates several downstream signals that mediate diabetic complications.4–8 Furthermore, advanced glycation end products formed by glucose-induced modification of proteins can act via their receptors such as RAGE and induce cellular oxidant stress, inflammation, and vascular dysfunction in diabetes.9–12 Recent evidence from laboratory and clinical studies demonstrates that diabetic atherosclerosis is not simply a disease of hyperlipidemia but also an inflammatory disorder involving multiple mediators such as C-reactive protein, cytokines such as tumor necrosis factor alpha, and interluekin-6 (IL-6).2,13,14 A recent gene profiling study showed that high glucose treatment of monocytes leads to increased expression of multiple inflammatory cytokines, chemokines, and related factors, many of which are regulated by the proinflammatory transcription factor, nuclear factor-kappa B (NF-B).15 The recognition now that highly effective antidiabetic agents, such as thiazolidinediones, and lipid-lowering agents, such as statins, possess antiinflammatory properties underscores the major role played by inflammatory mediators in the cardiovascular complications of diabetes. However, although the actions of inflammatory peptide growth factors, cytokines, and acute phase reactants have been fairly well studied, much less is known about the actions of the oxidized lipids and eicosanoids generated by these factors during cellular activation. These oxidized lipids, generated by the action of the lipoxygenase and cyclooxygenase enzymes, are produced under diabetic conditions and have potent proatherogenic effects in vessel wall cells. This review highlights the role of these pathways and their lipid products in the pathogenesis of diabetic vascular disease.
The Cyclooxygenase and Lipoxygenase Pathways
When growth factors and cytokines bind to their cell surface receptors, they can activate several phospholipases, which act on membrane phospholipids to release arachidonic acid, a precursor for several eicosanoids with potent biological effects.16,17 Arachidonic acid can be metabolized by 3 major oxidative pathways: the cyclooxygenase (COX) pathway that forms prostaglandins; the lipoxygenase (LO) pathway, which forms hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and thirdly, the cytochrome P-450 monooxygenase pathway that forms epoxides and HETEs18 (Figure 1). Products of the cytochrome P450 metabolic pathway have potent vasoactive properties, particularly in the kidney,19 but there are no reports of their involvement in diabetic vascular disease. COX-1 and COX-2 enzymes catalyze the first step in the biosynthesis of prostaglandins (PGs) by converting arachidonic acid to PGH2.20–24 PGH2 is further converted into other PGs and eicosanoids such as PGE2, PGD2, PGF2, PGI2 (prostacyclin), and thromboxane18,20 (Figure 1). COX-1 is constitutively expressed in most cells and plays a role in basal physiological functions in several cells and tissues. COX-2, however, is usually expressed at low or undetectable levels in most tissues and cells but is significantly induced by stimuli such as lipopolysaccharide, cytokines such as interleukin (IL)-1, IL-1?, and tumor necrosis factor-, and by growth factors.20–24 An exception is seen in some tissues,24 including the pancreatic islet that constitutively and dominantly expresses COX-2,25,26 and where its products such as PGE2 are believed to play a role in inflammation, islet destruction, and inhibition of insulin secretion associated with type 1 diabetes.25–28 COX-2 and its products also have renal functions and vascular effects.29,30 They are implicated in the pathogenesis of several inflammatory diseases, and selective inhibition of COX-2 is effective in reversing inflammation without gastric side effects.20,21,24,30 Although COX-2 can form the vasodilatory and protective prostacyclin, it also produces the potent inflammatory prostaglandin, PGE2.21–24
Figure 1. Metabolism of arachidonic acid. The cellular actions of growth factors, cytokines, and other agonists can lead to the activation phospholipases and thereby release arachidonic acid. Arachidonic acid can then be metabolized by the cyclooxygenase, lipoxygenase, and cytochrome P-450 enzymes to various bioactive molecules. Note that certain LO enzymes, including 12- and 15-LO, can also react with other fatty acid substrates, such as linoleic acid, to yield additional products.
The lipoxygenase (LOs) are mainly classified as 5-, 8-, 12- or 15-LO, based on their ability to insert molecular oxygen at the corresponding carbon position of arachidonic acid (Figure 1). 31–33 The 5-LO pathway leads to the formation of 5(S)-HETE and leukotrienes. Proinflammatory leukotrienes have been implicated in the pathogenesis of atherosclerosis, but very little is known regarding their role in diabetes. The 12- and 15-LOs can form 12(S)- and 15(S)-HETEs from arachidonic acid. The production of 12(S)- and 15(S)-HETE has been shown in several vascular tissues and cells, including cultured vascular smooth muscle cells (VSMC), endothelial cells, and monocytes. LO products may play important roles in the pathogenesis of hypertension, atherosclerosis, and diabetes, as discussed more in detail later in the review. Functionally distinct isoforms of 12-LO have been cloned, including platelet, leukocyte, and epidermal 12-LOs.31–37 Human and rabbit 15-LOs and the leukocyte 12-LO have high homology and are classified as 12/15-LOs because they can form both 12(S)-HETE and 15(S)-HETE from arachidonic acid via their hydroperoxy precursors and mainly hydroperoxyocatadecadienoic acids and hydroxyocatadecadienoic acids from linoleic acid.31,38 The 12/15-LO has been detected in porcine leukocytes,34 VSMC,39 endothelial cells,40–42 and in several rat and mouse tissues.43–45
The Cyclooxygenase Pathway in Diabetic Vascular Disease
COX-2 and its proinflammatory products have been implicated in the pathogenesis of several inflammatory diseases including atherosclerosis because COX-2 products such as PGE2 and thromboxane have potent proinflammatory and vasoconstrictor properties.20–24,46 Furthermore, augmented expression of COX-2 was noted in atherosclerotic lesions,47 and COX-2 could promote lesion formation in low-density lipoprotein (LDL) receptor-deficient mice.48 Because COX-2 inhibitors also block formation of the protective prostacyclin (PGI2), studies have been performed to determine whether these inhibitors could worsen atherosclerosis.30 Earlier studies showed that elevated glucose can stimulate the generation of endothelium-derived vasoconstrictor prostanoids such as thromboxane-A2.49 However, the potential involvement of COX-2 in diabetic vascular complications, diabetic atherosclerosis, or the regulation of COX-2 in relevant cells under diabetic conditions is only now becoming evident. In endothelial cells, high-glucose (HG) treatment increased COX-2 expression and decreased nitric oxide availability.50 Very recently, COX-2 activity and expression were shown to be upregulated by high glucose as well as ligands of the receptor for advanced glycation end products (RAGE) in monocytes, and this appeared to be primarily mediated by NF-B activation.51,52 Increased oxidant stress and protein kinase C activation under diabetic conditions could be contributory factors. Interestingly, COX-2 expression was also markedly increased in monocytes from diabetic patients.51,52 Furthermore, new data show that diabetic conditions can lead to chromatin remodeling and histone acetylation at the COX-2 gene promoter at NF-B binding sites.53 COX-2 also seemed to mediate monocyte adhesive interactions.51 A recent report demonstrated that in humans, RAGE overexpression is associated with enhanced inflammatory reactions and COX-2 expression in diabetic plaque macrophages, and that this effect could also contribute to plaque destabilization by inducing metalloproteinase expression.54 There was a significant correlation between plasma levels of hemoglobin A1c and RAGE and COX-2 expression. These results suggest that apart from its documented role in pancreatic islet dysfunction, COX-2 may be a key inflammatory mediator in the pathogenesis of diabetic atherosclerosis. Thus, the diabetic state can increase COX-2 expression and activity in vascular cells and monocytes and thereby aggravate downstream inflammatory and vascular events. It is also possible that 12/15-LO activation can increase COX-2 transcription based on studies in pancreatic islet beta cells.55
The Lipoxygenase Pathway in Atherosclerosis, Restenosis, Diabetes, and Insulin Resistance
LO enzymes and their products, namely HETEs and hydroxyocatadecadienoic acids, have been implicated in the pathogenesis of atherosclerosis. The 12/15-LO enzyme can mediate the oxidative modification of low-density lipoprotein (LDL) to the atherogenic oxidized LDL.56,57 Furthermore, angiotensin II (AII) could increase macrophage-mediated modification of LDL via the 12/15-LO pathway.58 Animal models have demonstrated the key role of the LO pathway in the pathogenesis of atherosclerosis and restenosis. Overexpression of 15-LO in the vascular endothelium could accelerate atherosclerosis in LDL receptor-deficient mice.59 Leukocyte-type 12/15-LO mRNA and protein were observed in porcine atherosclerotic lesions, which were greatly augmented in diabetic and hyperlipemic pigs displaying accelerated atherosclerosis.60 LO activation may also play a role in neointimal thickening associated with restenosis because there was a marked increase in 12/15-LO expression in balloon-injured rat carotid arteries relative to uninjured. Furthermore, pretreatment with a ribozyme targeted to rat 12/15-LO could significantly reduce neointimal thickening in this rat model.61 Convincing evidence supporting a pathological role for leukocyte 12/15-LO in atherosclerosis comes from recent reports showing marked decrease in atherosclerosis in apo E–/– mice and LDLR–/– that were cross-bred with leukocyte 12/15-LO–/– mice.62,63 Furthermore, a novel inflammatory link was suggested because the macrophages from 12/15-LO–/– mice had a selective defect in lipopolysaccharide-induced IL-12 synthesis.64 An interesting genetic study suggests that 5-LO may be an important proatherogenic gene locus.65 Also, 5-LO was abundantly expressed in atherosclerotic lesions,66 and it has been suggested that 5-LO may mediate specific stages of atherosclerosis.67 However, the role of 5-LO in diabetic vascular disease is not yet known. Overall, available evidence suggests that the LOs can contribute to the pathology of atherosclerosis and diabetic vascular disease by virtue of their capacity to oxidize LDL, to induce growth and inflammatory events, and by being in an atherogenic gene locus. The relative importance of the different LOs in this regard is not yet clear. Because the 12/15-LO pathway can be upregulated by hyperglycemia, growth factors, and cytokines, it is likely that it can augment diabetic atherosclerosis and vice versa, thereby setting off a vicious loop of events.
HG culture enhanced 12/15-LO pathway activation and expression in VSMC39 and endothelial cells.42 Furthermore, AII-induced 12/15-LO activity in VSMC was greater in HG relative to normal glucose.39 Apart from AII, 12/15-LO activity and expression in VSMC could also be potently upregulated by platelet-derived growth factor (PDGF) BB and by cytokines such as IL-1, IL-4, and IL-8 in VSMC.68,69 The 15-LO expression was induced in monocytes and endothelial cells by IL-4 or IL-13.41,70–72 Thus, 12/15-LO in vascular and mononuclear cells can be induced by diabetic conditions, growth factors, and cytokines, and may contribute to their biological and atherogenic effects.
The LO pathway may therefore play a role in the cardiovascular complications associated with diabetes. Endothelial cells and VSMC cultured under hyperglycemic conditions produced increased amounts of HETEs.39,42,73 Furthermore, HG-induced adhesion of monocytes to endothelial cells could be mediated by the LO pathway.42,74 The 12/15-LO products also appear to mediate minimally modified LDL-induced monocyte binding to endothelial cells.75 LO products have potent chemotactic and hypertrophic effects in VSMC.76–78 The hypertrophic effects of 12(S)-HETE in VSMC were markedly enhanced under HG culture conditions in a manner similar to those of angiotensin II.77 There is now considerable evidence to support a role for 12/15-LO in promoting the development of diabetes and atherosclerosis. Bleich et al noted that 12/15-LO–deficient mice were resistant to the development of diabetes.79 In vivo relevance of 12/15-LO in human diabetes was suggested by a study demonstrating increased urinary excretion of 12(S)-HETE in diabetic subjects compared with matched nondiabetic controls.80 Interestingly, these diabetic subjects also had decreased urinary prostacyclin levels, suggesting a potential shunting into the 12/15-LO pathway. Recently, increased 12/15-LO expression was noted in a swine model of hyperlipidemia and diabetes-induced accelerated atherosclerosis.60 Diabetes and hyperlipidemia alone increased both monocyte oxidant stress and 12/15-LO expression in arteries, but the combination of these 2 risk factors in this swine model led to not only a marked acceleration of atherosclerosis but also a synergistic increase in oxidant stress and 12/15-LO activation.60 A recent report demonstrated increased expression of 12/15-LO in urine and endothelial cells from diabetic db/db mice.81 Interestingly, it was noted that the increased production of 12/15-LO products by the endothelial cells of the db/db mice was responsible for the observed increased in binding of monocytes to the endothelial cells from db/db versus those from control mice, and it was concluded that the 12/15-LO pathway is important for mediating early vascular changes and inflammatory reactions in diabetes.81 Taken together, these results suggest an in vivo role for leukocyte type 12/15-LO in diabetic atherosclerosis.
Emerging evidence supports a clear role of insulin resistance and diabetes in leading to accelerated cardiovascular disease. As discussed, elevated glucose and diabetes increase the expression and activity of 12/15-LO. However, fewer reports have evaluated the role of 12/15-LO in metabolic disturbances seen in the insulin resistance syndrome. Of interest are studies showing that masoprocol, a LO inhibitor, can reduce triglycerides, free fatty acids, and improve insulin action in both fructose-fed and fat-fed rat models of insulin resistance and type 2 diabetes.82,83 In addition, 12-LO products can downregulate glucose transport in VSMC.84 To further evaluate the effect of insulin resistance on vascular injury responses and 12/15-LO expression, we studied the effect of carotid balloon injury in lean and obese insulin-resistant Zucker rats. After injury, the intima-to-media ratio of obese Zucker rats was significantly greater than leans starting at 14 days after injury and persisting up to at least day 30. The expression of inflammatory mediators including 12/15-LO and IL-6 were markedly increased in obese compared with lean animals suggesting that vascular injury in obese Zucker rats is associated with inflammation. Increased macrophage and p-selectin staining was also seen. These studies (unpublished) indicate an exaggerated injury response in the insulin resistant obese Zucker rat model and that inflammation may play a major role in mediating neointimal growth under these conditions. In addition, 12/15-LO was one of the few genes upregulated in the pancreatic beta cell of the insulin resistant prediabetic Zucker diabetic fatty rat,85 thereby suggesting that 12/15-LO expression is enhanced in the prediabetic metabolic syndrome condition before frank hyperglycemia. Thus 12/15-LO may have a role in the excess cardiovascular disease seen even before diabetes is diagnosed. Because hyperglycemia alone also increases 12/15-LO expression in vascular cells, it is likely that 12/15-LO can participate in the development of type 2 diabetes and atherosclerosis, whereas the associated hyperglycemia, dyslipidemia, and insulin resistance can further augment 12/15-LO pathway activation to set off a vicious loop of inflammatory events. Furthermore, factors such as growth factors, cytokines, and advanced glycation end products, all of which are relevant to the pathogenesis of diabetes, can also upregulate the activity and expression of 12/15-LO (Figure 2).
Figure 2. Actions of 12/15-LO in the vessel wall. Induction of 12/15-LO and its products in endothelial cells by factors such as HG and AGEs can lead to oxidant stress, release of chemokines, activation of monocyte integrins, and key endothelial adhesive molecules and thereby lead to endothelial dysfunction, monocyte activation, and adhesion. In VSMC, similarly, 12/15-LO and its products can induce oxidant stress, adhesion molecules, extracellular matrix proteins, release of inflammatory cytokines, and chemokines, thereby leading to VSMC hypertrophy, migration, and inflammatory responses. 12/15-LO in monocyte/macrophages, endothelial cells, and VSMC can mediate LDL oxidation to oxidized LDL.
Lipoxygenase Products Have Growth, Chemotactic, Adhesive, and Inflammatory Effects in VSMC and Endothelial Cells
Treatment of human aortic endothelial cells with 12(S)-HETE, but not 12(R)-HETE, increased monocyte binding to the endothelial cells, a key early step in the development of atherosclerosis.74 Furthermore, the 12/15-LO ribozyme blocked high-glucose–induced binding of monocytes to endothelial cells, suggesting that glucose-induced LO activation in endothelial cells may lead to endothelial activation and dysfunction.42 The 12(S)-HETE increased the expression of CS-1 fibronectin on endothelial cells, which could be a key mechanism for inducing monocyte adhesion. Certain LO products also increased the surface expression of key inflammatory adhesion molecules such as VCAM-1 via activation of the transcription factor, NF-B.86,87 LO products also directly increased migration, cellular hypertrophy, and fibronectin synthesis in VSMC.76–78 Angiotensin II (AII)-induced increases in total cellular protein content of porcine VSMC were significantly attenuated by a specific LO inhibitor.77 Furthermore, direct addition of the 12-LO product, 12(S)-HETE, increased total cell protein content and fibronectin levels to nearly the same extent as AII.77,78 A rat 12/15-LO ribozyme could significantly inhibit HG-induced fibronectin production.61 Because AII and HG culture can increase the formation of LO products, it is attractive to speculate that the enhanced growth-promoting and matrix effects of the LO products formed by AII and HG are potential mechanisms for the accelerated growth of VSMC and enhanced hypertrophic effects of AII under HG conditions. In support of this, it was noted that rat VSMC and cardiac fibroblasts stably expressing mouse 12/15-LO showed increased growth properties.78,88 In addition, pharmacological LO inhibitors, as well as the 12/15-LO ribozyme, could also significantly inhibit PDGF-induced migration of VSMC.42,68 Because PDGF can upregulate 12/15-LO,68 LO activation may mediate, at least in part, the chemotactic effects of PDGF.
LO products also have proinflammatory effects in VSMC. Thus the 12/15-LO product of linoleic acid, 13-HPODE, led to a significant increase in the activation of the redox-sensitive and inflammatory transcription factor, NF-B in VSMC.87 This was associated with increased transcription of the inflammatory adhesion molecule VCAM-1 and the potent chemokines monocyte chemoattractant protein-1 via an NF-B–dependent mechanism.87,89
Signal Transduction and Gene Regulation Mechanisms by Which LO Products Mediate Their Cellular Actions
HETEs can activate certain isoforms of protein kinase C directly or indirectly by incorporating into membrane phospholipids, which then generate HETE-containing diacylglycerol species to activate protein kinase C.90 They can also activate several mitogen activated protein kinases (MAPKs) and thereby activate key transcription factors that mediate the expression of growth and inflammatory genes.78,90 In VSMC, 12(S)-HETE could lead to the transcription of the fibronectin gene, and this was regulated by the transcription factor CREB in a p38MAPK-dependent manner.78 However, the hydroperoxy LO product, 13(S)-HPODE, could increase the expression of VCAM-1 in an NF-B–dependent manner and partly via p38MAPK.87 Thus these oxidized lipids can serve as novel signal transducers, regulators, and amplifiers of gene induction by high glucose, growth factor, and cytokine actions. Interestingly, a novel role for HPODE and hydroperoxy precursor as seeding molecules responsible for LDL oxidation by artery wall cells and associated oxidative events related to the pathogenesis of atherosclerosis has been demonstrated.91 In monocytes, 9-hydroxyocatadecadienoic acid and 13-hydroxyocatadecadienoic acid (12/15-LO products of linoleic acid metabolism) induced the expression of the scavenger receptor, CD36, apparently via activation of the nuclear receptor, peroxisome proliferator activator-gamma.92 IL-4–induced 12/15-LO activation was also implicated in this process.93
Coffey et al demonstrated that 12/15-LO can lead to the catalytic consumption of the vasodilator, nitric oxide, and prevent nitric oxide-mediated soluble guanylate cyclase activation.94 This suggests that 12/15-LO may mediate the pathology of vascular diseases such as atherosclerosis, hypertension, and diabetes not only by the bioactivity of their lipid products but also by limiting the availability of nitric oxide in the vessel wall. Reactive oxygen species generated during LO pathway activation95 may mediate growth and inflammatory effects in VSMC and endothelial cells. Conversely, high-glucose induced oxidant stress, and reactive oxygen species in diabetes can lead to the induction of 12/15-LO in VSMC and endothelial cells and promote cellular dysfunction. Recent reports show that VSMC derived from 12/15-LO–/– mice grow slower than those derived from genetic control mice, produce much lesser amounts of superoxide, and have reduced activation of MAPKs,96 whereas endothelial cells derived from these 12/15-LO KO mice display decreased binding to monocytes compared with those from control mice.97 However, new data show that endothelial cells from 12/15-LO transgenic mice reciprocally display enhanced monocyte binding relative to those from control mice.97 Interestingly, these 12/15-LO transgenic mice also developed more atherosclerotic lesions.97 Overall, it appears that 12/15-LO can participate in an inflammatory loop with cytokines and other inflammatory genes to amplify or modulate their cellular responses and thereby accelerate the development of cardiovascular complications in diabetes.
In summary, LO and COX-2 enzymes in vascular, inflammatory, and other cells can form products with pleiotropic physiological and pathological effects. These include vasoactive, growth, adhesive, chemotactic, oxidative, and inflammatory responses, which therefore implicate them in the pathogenesis of diabetic vascular disease such as atherosclerosis and hypertension. Although COX-2–specific inhibitors are now available for clinical use, there are currently no clinically safe, pharmacologically selective, and optimally bioavailable inhibitors of 12/15-LO. Hence, the development of 12/15-LO inhibitors, including novel ribozymes, may lead to new antiinflammatory therapies for diabetic vascular complications.
Acknowledgments
We acknowledge grant support from the National Institutes of Health (PO1 HL55798, RO1 DK55240, RO1 DK065073, and RO1 DK58191) and the Juvenile Diabetes Research Foundation International. We thank Dr Q. Cai for his help with the manuscript.
References
Beckman JA, Craeger MA, Libby P. Diabetes and atherosclerosis. epidemiology, pathophysiology, and management. JAMA. 2002; 287: 2570–2581.
Libby P, Plutzky J. Diabetic macrovascular disease. The glucose paradox? Circulation. 2002; 106: 2760–2763.
Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001; 286: 1195–1200.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414: 813–820.
Ido Y, Kilo C, Williamson JR. Cytosolic NADH/NAD+, free radicals, and vascular dysfunction in early diabetes mellitus. Diabetologia. 1997; 40 (suppl 2): S115–S117.
Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M. Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003; 112: 1049–1057.
Way KJ, Katai N, King GL. Protein kinase C and the development of diabetic vascular complications. Diabet Med. 2001; 18: 945–959.
Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991; 87: 1643–1648.
Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988; 318: 1315–1321.
Schmidt A, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arteriosclerosis Thromb. 1994; 14: 1521–1528.
Schmidt AM, Hori O, Chen J, Li JF, Crandall J, Zhang J, Cao R, Yan SD, Brett J, and Stern D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1): a potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995; 96: 1395–1403.
Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, Hori O, Stern D, Schmidt AM. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest. 1996; 97: 238–243.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.
Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002; 36: 1331–1336.
Shanmugam N, Reddy MA, Guha M, Natarajan R. High Glucose induced expression of pro-inflammatory cytokine and chemokine genes in monocytic cells. Diabetes. 2003; 52: 1256–1264.
Liscovitch M. Crosstalk among multiple signal-activated phospholipases. Trends Biochem Sci. 1992; 17: 393–399.
Di Marzo V. Arachidonic acid and eicosanoids as targets and effectors in second messenger interactions. Prostaglandins Leukot Essent Fatty Acids. 1995; 53: 239–254.
Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J. 1989; 259: 315–324.
Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002; 82: 131–185.
Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. Advances Immunol. 1996; 62: 167–215.
Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human Monocytes. J Biol Chem. 1990; 265: 16737–16740.
Herschman HR. Prostaglandin Synthase 2. Biochim Biophys Acta. 1996; 1299: 125–140.
Hla T, Ristimaki A, Appleby SB, Barriocanal JG. Cyclooxygenase gene expression in inflammation and angiogenesis. Ann N Y Acad Sci. 1993; 696: 197–204.
Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol. 1998; 38: 97–120.
Robertson RP. Dominance of cyclooxygenase-2 in the regulation of pancreatic islet prostaglandin synthesis. Diabetes. 1998; 47: 1379–1383.
McDaniel ML, Kwon G, Hill JR, Marshall CA, Corbett JA. Cytokines and nitric oxide in islet inflammation and diabetes. Proc Soc Exp Biol Med. 1996; 211: 24–32.
Tran PO, Gleason CE, Poitout V, Robertson RP. Prostaglandin E (2) mediates inhibition of insulin secretion by interleukin-1beta. J Biol Chem. 1999; 274: 31245–31248.
Kwon G, Corbett JA, Hauser S, Hill JR, Turk J, McDaniel ML. Evidence for involvement of the proteasome complex (26S) and NF-kappaB in IL-1?-induced nitric oxide and prostaglandin production by rat islets and RINm5F cells. Diabetes. 1998; 47: 583–591.
Harris RC, McKanna JA, Akai Y, Jacoban HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994; 94: 2504–2510.
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96: 272–277.
Yamamoto S. Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta. 1992; 1128: 117–131.
Kuhn H, Thiele BJ. The diversity of the lipoxygenase family. Many sequence data but little information on biological significance. FEBS Lett. 1999; 449: 7–11.
Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice. Biochim Biophys Acta. 1996; 1304: 65–84.
Yoshimoto T, Suzuki H, Yamamoto S, Takai T, Yokoyama C, Tanabe T. Cloning and sequence analysis of the cDNA for arachidonate 12-lipoxygenase of porcine leukocytes. Proc Natl Acad Sci U S A. 1990; 87: 2142–2146.
Sigal E. The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol. 1991; 260: L13–L28.
Funk CD, Furci L, FitzGerald. Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase. Proc Natl Acad Sci U S A. 1990; 87: 5638–5642.
Izumi T, Hoshiko S, Radmark O, Samuelsson B. Cloning of the cDNA for human 12-lipoxygenase. Proc Natl Acad Sci U S A. 1990; 87: 7477–7481.
Sigal E, Craik CS, Highland E, Grunberger D, Costello LL, Dixon RA, Nadel JA. Molecular cloning and primary structure of human 15-lipoxygenase. Biochem Biophys Res Commun. 1988; 157: 457–464.
Natarajan R, Gu JL, Rossi J, Gonzales N, Lanting L, Xu L, Nadler J. Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1993; 90: 4947–4951.
Kim JA, Gu JL, Natarajan R, Berliner JA, Nadler JL. A leukocyte type of 12-lipoxygenase is expressed in human vascular and mononuclear cells. Evidence for upregulation by angiotensin II. Arterioscler Thromb Vasc Biol. 1995; 15: 942–948.
Lee YW, Kuhn H, Kaiser S, Hennig B, Daugherty A, Toborek M. Interleukin 4 induces transcription of the 15-lipoxygenase I gene in human endothelial cells. J Lipid Res. 2001; 42: 783–791.
Patricia MK, Natarajan R, Dooley AN, Hernandez F, Gu JL, Berliner JA, Rossi JJ, Nadler JL, Meidell RS, Hedrick CC. Adenoviral delivery of a leukocyte-type 12-lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells. Circ Res. 2001; 88: 659–665.
Watanabe T, Medina JF, Haeggstrom JZ, Radmark O, Samuelsson B. Molecular cloning of a 12-lipoxygenase cDNA from rat brain. Eur J Biochem. 1993; 212: 605–612.
Katoh T, Lakkis FG, Makita N, Badr KF. Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Kidney Int. 1994; 46: 341–349.
Chen XS, Kurre U, Jenkins NA, Copeland NG, Funk CD. cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localizations of murine 12-lipoxygenases. J Biol Chem. 1994; 269: 13979–13987.
Linton MF, Fazio S. Cyclooxygenase-2 and inflammation in atherosclerosis. Curr Opin Pharmacol. 2004; 4: 116–123.
Schonbeck U, Sukhova G, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999; 155: 1281–1291.
Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002; 105: 1816–1823.
Tesfamariam B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest. 1990; 85: 929–932.
Cosentino F, Eto M, De Paolis P, van der Loo B, Bachschmid M, Ullrich V, Kouroedov A, Gatt CD, Joch H, Volpe M, Luscher TF. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation. 2003; 107: 1017–1023.
Shanmugam N, Kim YS, Lanting L, Natarajan R. Regulation of cyclooxygenase-2 expression in monocytes by ligation of the receptor for advanced glycation end products. J Biol Chem. 2003; 278: 34834–34844.
Shanmugam N, Gaw-Gonzalo I, Natarajan R. Molecular mechanisms of high glucose-induced COX-2 regulation in monocytes. Diabetes. 2004; 53: 795–802.
Miao F, Gonzalo IG, Lanting L, Natarajan R. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J Biol Chem. 2004; 279: 18091–18097.
Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003; 108: 1070–1077.
Han X, Chen S, Sun Y, Nadler JL, Bleich D. Induction of cyclooxygenase-2 gene in pancreatic beta cells by 12-lipoxygenase pathway product 12-hydroxyeicosatetraenoic acid. Mol Endocrinol. 2002; 16: 2145–2154.
Parthasarathy S, Wieland E, Steinberg D. A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. Proc Natl Acad Sci U S A. 1989; 86: 1046–1050.
Folcik VA, Nivar-Aristy RA, Krajewski LP, Cathcart MK. Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J Clin Invest. 1995; 96: 504–510.
Scheidegger KJ, Butler S, Witztum JL. Angiotensin II increases macrophage-mediated modification of low-density lipoprotein via a lipoxygenase-dependent pathway. J Biol Chem. 1997; 272: 21609–21615.
Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H, Sigal E. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20: 2100–2105.
Natarajan R, Gerrity RG, Gu JL, Lanting L, Thomas L, Nadler JL. Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model. Diabetologia. 2002; 45: 125–133.
Gu JL, Pei H, Thomas L, Nadler JL, Rossi JJ, Lanting L, Natarajan R. Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries. Circulation. 2001; 103: 1446–1452.
Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999; 103: 1597–1604.
George J, Afek A, Shaish A, Levkovitz H, Bloom N, Cyrus T, Zhao L, Funk CD, Sigal E, Harats D. 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation. 2001; 104: 1646–1650.
Zhao L, Cuff CA, Moss E, Wille U, Cyrus T, Klein EA, Pratico D, Rader DJ, Hunter CA, Pure E, Funk CD. Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol Chem. 2002; 277: 35350–35356.
Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z, Funk CD, Lusis AJ, Shih W. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002; 91: 120–126.
Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Hadenicht AJ. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci U S A. 2003; 100: 1238–1243.
Mehrabian M, Allayee H. 5-Lipoxygenase and atherosclerosis. Curr Opin Lipidol. 2003; 14: 447–457.
Natarajan R, Bai W, Rangarajan V, Gonzales N, Gu JL, Lanting L, Nadler JL. Platelet-derived growth factor BB mediated regulation of 12-lipoxygenase in porcine aortic smooth muscle cells. J Cell Physiol. 1996; 169: 391–400.
Natarajan R, Rosdahl J, Gonzales N, Bai W. Regulation of 12-lipoxygenase by cytokines in vascular smooth muscle cells. Hypertension. 1997; 30: 873–879.
Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci U S A. 1992; 89: 217–221.
Nassar GM, Morrow JD, Roberts LJ, 2nd, Lakkis FG, Badr KF. Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. J Biol Chem. 1994; 269: 27631–27634.
Roy B, Cathcart MK. Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of Jak2 and Tyk2 in human monocytes. J Biol Chem. 1998; 273: 32023–32029.
Brown ML, Jakubowski JA, Leventis LL, Deykin D. Elevated glucose alters eicosanoid release from porcine aortic endothelial cells. J Clin Invest. 1988; 82: 2136–2141.
Patricia MK, Kim JA, Harper CM, Shih PT, Berliner JA, Natarajan R, Nadler JL, Hedrick CC. Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 2615–2622.
Honda HM, Leitinger N, Frankel M, Goldhaber JI, Natarajan R, Nadler JL, Weiss JN, Berliner JA. Induction of monocyte binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites. Arterioscler Thromb Vasc Biol. 1999; 19: 680–686.
Nakao J, Ooyama T, Ito H, Chang WC, Murota S. Comparative effect of lipoxygenase products of arachidonic acid on rat aortic smooth muscle cell migration. Atherosclerosis. 1982; 44: 339–342.
Natarajan R, Gonzales N, Lanting L, Nadler J. Role of the lipoxygenase pathway in angiotensin II-induced vascular smooth muscle cell hypertrophy. Hypertension. 1994; 23: I142–I147.
Reddy MA, Thimmalapura PR, Lanting L, Nadler JL, Fatima S, Natarajan R. The oxidized lipid and lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid induces hypertrophy and fibronectin transcription in vascular smooth muscle cells via p38 MAPK and cAMP response element-binding protein activation. Mediation of angiotensin II effects. J Biol Chem. 2002; 277: 9920–9928.
Bleich D, Chen S, Zipser B, Sun D, Funk CD, Nadler JL. Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J Clin Invest. 1999; 103: 1431–1436.
Antonipillai I, Nadler J, Vu EJ, Bughi S, Natarajan R, Horton R. A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease. J Clin Endocrinol Metab. 1996; 81: 1940–1945.
Hatley ME, Srinivasan S, Reilly KB, Bolick DT, Hedrick CC. Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. J Biol Chem. 2003; 278: 25369–25375.
Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Brignetti D, Luo J, Khandwala A, Reaven GM. Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type 2 diabetes. Diabetologia. 1999; 42: 102–106.
Scribner K, Gadbois T, Gowri M, Azhar Sl, Reaven G. Masoprocol decreases serum triglyceride concentration in rats with fructose-induced hypertriglyceridemia. Metabolism. 2000; 9: 1106–1110.
Alpert E, Gruzman A, Totary H, Kaiser N, Reich R, Sasson S. A natural protective mechanism against hyperglycemia in vascular endothelial and smooth muscle cells: role of glucose and 12-hydroxyeicosatetraenoic acid. Biochem J. 2002; 362: 413–422.
Tokuyama Y, Sturis J, DePaoli AM, Takeda J, Stoffel M, Tang J, Sun X, Polonsky KS, Bell GI. Evolution of beta cell dysfunction in the male Zucker diabetic fatty rat. Diabetes. 1995; 44: 1447–1457.
Sultana CY, Shen V, Rattan V, Kalra K. Lipoxygenase metabolites induced expression of adhesion molecules and transendothelial migration of monocyte-like HL-60 cells is linked to protein kinase C activation. J Cell Physiol. 1996; 167: 477–487.
Natarajan R, Reddy MA. Malik KU, Fatima S, Khan BV. Signaling mechanisms of nuclear factor-kappab-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21: 1408–1413.
Wen Y, Gu J, Peng X, Zhang G, Nadler JL. Overexpression of 12-lipoxygenase and cardiac fibroblast hypertrophy. Trends in Cardiovasc Med. 2003; 134: 129–136.
Dwarakanath RS, Sahar S, Reddy MA, Castanotto D, Rossi JJ, Natarajan R. Regulation of monocyte chemoattractant protein-1 by the oxidized lipid,13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kB). Mol Cell Cardiol. 2004; 36: 585–595.
Natarajan R, Nadler JL. Lipoxygenases and Lipid Signaling in Diabetes. Frontiers in Biosciences. 2003; 8: S783–S795.
Navab M, Hama SY, Cooke CJ, Anantharamaiah GM, Chaddha M, Jin L, Subbanagounder G, Faull KF, Reddy ST, Miller NE, Fogelman AM. Normal high-density lipoprotein inhibits three steps in the formation of mildly oxidized low-density lipoprotein: step 1. J Lipid Res. 2000; 41: 1481–1494.
Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998; 93: 241–252.
Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR- ligands in macrophages by 12/15-lipoxygenase. Nature. 1999; 400: 378–382.
Coffey MJ, Natarajan R, Chumley PH, Coles B, Thimmalapura PR, Nowell M, Kuhn H, Lewis MJ, Freeman BA, O’Donnell VB. Catalytic consumption of nitric oxide by 12/15- lipoxygenase: inhibition of monocyte soluble guanylate cyclase activation. Proc Natl Acad Sci U S A. 2001; 98: 8006–8011.
Roy P, Roy SK, Mitra A, Kulkarni AP. Superoxide generation by lipoxygenase in the presence of NADH and NADPH. Biochim Biophys Acta. 1994; 1214: 171–179.
Reddy MA, Kim YS, Lanting L, Natarajan R. Reduced growth factor responses in vascular smooth muscle cells derived from 12/15-lipoxygenase deficient mice. Hypertension. 2003; 41: 1294–1300.
Reilly KB, Srinivasan S, Hatley ME, Kim Patricia M, Lannigan J, Bolick DT, Vandenhoff G, Pei H, Natarajan R, Nadler JL, Hedrick CC. 12/15 lipoxygenase activity mediates inflammatory monocyte: endothelial interactions and atherosclerosis in vivo. J Biol Chem. 2003; 279: 9440–9450.(Rama Natarajan; Jerry L. )
Series Editor: Richard A. Cohen
ATVB in Focus
Diabetic Vascular Disease: Pathophysiological Mechanisms in the Diabetic
Milieu and Therapeutic Implications
Previous Brief Review in this Series:
?Naka Y, Bucciarelli LG, Wendt T, Lee LK, Rong LL, Ramasamy R, Yan SF, Schmidt AM. RAGE axis: animal models and novel insights into the vascular complications of diabetes. 2004;24:1342–1349.
ABSTRACT
Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease.
Evidence suggests that inflammatory responses in the vasculature can be elicited by small oxidized lipids that are components of oxidized low-density lipoprotein or products of the lipoxygenase and cyclooxygenase pathways of arachidonic and linoleic acid metabolism. This review evaluates these inflammatory and proatherogenic pathways in the pathogenesis of diabetic vascular disease.
Key Words: lipoxygenase ? diabetes ? diabetes complications ? inflammation ? lipids
Introduction
Diabetes is associated with significantly accelerated rates of cardiovascular complications such as atherosclerosis and hypertension. In particular, type 2 diabetes is associated with 2- to 4-fold increase in coronary artery disease.1 This has been attributed to the clustering of several risk factors, including insulin resistance, hypertension, obesity, and dyslipidemia.2,3 Multiple mechanisms contribute to vascular and arterial disease in the diabetic population.2 Basic biochemical mechanisms have been described by which hyperglycemia-induced oxidant stress activates several downstream signals that mediate diabetic complications.4–8 Furthermore, advanced glycation end products formed by glucose-induced modification of proteins can act via their receptors such as RAGE and induce cellular oxidant stress, inflammation, and vascular dysfunction in diabetes.9–12 Recent evidence from laboratory and clinical studies demonstrates that diabetic atherosclerosis is not simply a disease of hyperlipidemia but also an inflammatory disorder involving multiple mediators such as C-reactive protein, cytokines such as tumor necrosis factor alpha, and interluekin-6 (IL-6).2,13,14 A recent gene profiling study showed that high glucose treatment of monocytes leads to increased expression of multiple inflammatory cytokines, chemokines, and related factors, many of which are regulated by the proinflammatory transcription factor, nuclear factor-kappa B (NF-B).15 The recognition now that highly effective antidiabetic agents, such as thiazolidinediones, and lipid-lowering agents, such as statins, possess antiinflammatory properties underscores the major role played by inflammatory mediators in the cardiovascular complications of diabetes. However, although the actions of inflammatory peptide growth factors, cytokines, and acute phase reactants have been fairly well studied, much less is known about the actions of the oxidized lipids and eicosanoids generated by these factors during cellular activation. These oxidized lipids, generated by the action of the lipoxygenase and cyclooxygenase enzymes, are produced under diabetic conditions and have potent proatherogenic effects in vessel wall cells. This review highlights the role of these pathways and their lipid products in the pathogenesis of diabetic vascular disease.
The Cyclooxygenase and Lipoxygenase Pathways
When growth factors and cytokines bind to their cell surface receptors, they can activate several phospholipases, which act on membrane phospholipids to release arachidonic acid, a precursor for several eicosanoids with potent biological effects.16,17 Arachidonic acid can be metabolized by 3 major oxidative pathways: the cyclooxygenase (COX) pathway that forms prostaglandins; the lipoxygenase (LO) pathway, which forms hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and thirdly, the cytochrome P-450 monooxygenase pathway that forms epoxides and HETEs18 (Figure 1). Products of the cytochrome P450 metabolic pathway have potent vasoactive properties, particularly in the kidney,19 but there are no reports of their involvement in diabetic vascular disease. COX-1 and COX-2 enzymes catalyze the first step in the biosynthesis of prostaglandins (PGs) by converting arachidonic acid to PGH2.20–24 PGH2 is further converted into other PGs and eicosanoids such as PGE2, PGD2, PGF2, PGI2 (prostacyclin), and thromboxane18,20 (Figure 1). COX-1 is constitutively expressed in most cells and plays a role in basal physiological functions in several cells and tissues. COX-2, however, is usually expressed at low or undetectable levels in most tissues and cells but is significantly induced by stimuli such as lipopolysaccharide, cytokines such as interleukin (IL)-1, IL-1?, and tumor necrosis factor-, and by growth factors.20–24 An exception is seen in some tissues,24 including the pancreatic islet that constitutively and dominantly expresses COX-2,25,26 and where its products such as PGE2 are believed to play a role in inflammation, islet destruction, and inhibition of insulin secretion associated with type 1 diabetes.25–28 COX-2 and its products also have renal functions and vascular effects.29,30 They are implicated in the pathogenesis of several inflammatory diseases, and selective inhibition of COX-2 is effective in reversing inflammation without gastric side effects.20,21,24,30 Although COX-2 can form the vasodilatory and protective prostacyclin, it also produces the potent inflammatory prostaglandin, PGE2.21–24
Figure 1. Metabolism of arachidonic acid. The cellular actions of growth factors, cytokines, and other agonists can lead to the activation phospholipases and thereby release arachidonic acid. Arachidonic acid can then be metabolized by the cyclooxygenase, lipoxygenase, and cytochrome P-450 enzymes to various bioactive molecules. Note that certain LO enzymes, including 12- and 15-LO, can also react with other fatty acid substrates, such as linoleic acid, to yield additional products.
The lipoxygenase (LOs) are mainly classified as 5-, 8-, 12- or 15-LO, based on their ability to insert molecular oxygen at the corresponding carbon position of arachidonic acid (Figure 1). 31–33 The 5-LO pathway leads to the formation of 5(S)-HETE and leukotrienes. Proinflammatory leukotrienes have been implicated in the pathogenesis of atherosclerosis, but very little is known regarding their role in diabetes. The 12- and 15-LOs can form 12(S)- and 15(S)-HETEs from arachidonic acid. The production of 12(S)- and 15(S)-HETE has been shown in several vascular tissues and cells, including cultured vascular smooth muscle cells (VSMC), endothelial cells, and monocytes. LO products may play important roles in the pathogenesis of hypertension, atherosclerosis, and diabetes, as discussed more in detail later in the review. Functionally distinct isoforms of 12-LO have been cloned, including platelet, leukocyte, and epidermal 12-LOs.31–37 Human and rabbit 15-LOs and the leukocyte 12-LO have high homology and are classified as 12/15-LOs because they can form both 12(S)-HETE and 15(S)-HETE from arachidonic acid via their hydroperoxy precursors and mainly hydroperoxyocatadecadienoic acids and hydroxyocatadecadienoic acids from linoleic acid.31,38 The 12/15-LO has been detected in porcine leukocytes,34 VSMC,39 endothelial cells,40–42 and in several rat and mouse tissues.43–45
The Cyclooxygenase Pathway in Diabetic Vascular Disease
COX-2 and its proinflammatory products have been implicated in the pathogenesis of several inflammatory diseases including atherosclerosis because COX-2 products such as PGE2 and thromboxane have potent proinflammatory and vasoconstrictor properties.20–24,46 Furthermore, augmented expression of COX-2 was noted in atherosclerotic lesions,47 and COX-2 could promote lesion formation in low-density lipoprotein (LDL) receptor-deficient mice.48 Because COX-2 inhibitors also block formation of the protective prostacyclin (PGI2), studies have been performed to determine whether these inhibitors could worsen atherosclerosis.30 Earlier studies showed that elevated glucose can stimulate the generation of endothelium-derived vasoconstrictor prostanoids such as thromboxane-A2.49 However, the potential involvement of COX-2 in diabetic vascular complications, diabetic atherosclerosis, or the regulation of COX-2 in relevant cells under diabetic conditions is only now becoming evident. In endothelial cells, high-glucose (HG) treatment increased COX-2 expression and decreased nitric oxide availability.50 Very recently, COX-2 activity and expression were shown to be upregulated by high glucose as well as ligands of the receptor for advanced glycation end products (RAGE) in monocytes, and this appeared to be primarily mediated by NF-B activation.51,52 Increased oxidant stress and protein kinase C activation under diabetic conditions could be contributory factors. Interestingly, COX-2 expression was also markedly increased in monocytes from diabetic patients.51,52 Furthermore, new data show that diabetic conditions can lead to chromatin remodeling and histone acetylation at the COX-2 gene promoter at NF-B binding sites.53 COX-2 also seemed to mediate monocyte adhesive interactions.51 A recent report demonstrated that in humans, RAGE overexpression is associated with enhanced inflammatory reactions and COX-2 expression in diabetic plaque macrophages, and that this effect could also contribute to plaque destabilization by inducing metalloproteinase expression.54 There was a significant correlation between plasma levels of hemoglobin A1c and RAGE and COX-2 expression. These results suggest that apart from its documented role in pancreatic islet dysfunction, COX-2 may be a key inflammatory mediator in the pathogenesis of diabetic atherosclerosis. Thus, the diabetic state can increase COX-2 expression and activity in vascular cells and monocytes and thereby aggravate downstream inflammatory and vascular events. It is also possible that 12/15-LO activation can increase COX-2 transcription based on studies in pancreatic islet beta cells.55
The Lipoxygenase Pathway in Atherosclerosis, Restenosis, Diabetes, and Insulin Resistance
LO enzymes and their products, namely HETEs and hydroxyocatadecadienoic acids, have been implicated in the pathogenesis of atherosclerosis. The 12/15-LO enzyme can mediate the oxidative modification of low-density lipoprotein (LDL) to the atherogenic oxidized LDL.56,57 Furthermore, angiotensin II (AII) could increase macrophage-mediated modification of LDL via the 12/15-LO pathway.58 Animal models have demonstrated the key role of the LO pathway in the pathogenesis of atherosclerosis and restenosis. Overexpression of 15-LO in the vascular endothelium could accelerate atherosclerosis in LDL receptor-deficient mice.59 Leukocyte-type 12/15-LO mRNA and protein were observed in porcine atherosclerotic lesions, which were greatly augmented in diabetic and hyperlipemic pigs displaying accelerated atherosclerosis.60 LO activation may also play a role in neointimal thickening associated with restenosis because there was a marked increase in 12/15-LO expression in balloon-injured rat carotid arteries relative to uninjured. Furthermore, pretreatment with a ribozyme targeted to rat 12/15-LO could significantly reduce neointimal thickening in this rat model.61 Convincing evidence supporting a pathological role for leukocyte 12/15-LO in atherosclerosis comes from recent reports showing marked decrease in atherosclerosis in apo E–/– mice and LDLR–/– that were cross-bred with leukocyte 12/15-LO–/– mice.62,63 Furthermore, a novel inflammatory link was suggested because the macrophages from 12/15-LO–/– mice had a selective defect in lipopolysaccharide-induced IL-12 synthesis.64 An interesting genetic study suggests that 5-LO may be an important proatherogenic gene locus.65 Also, 5-LO was abundantly expressed in atherosclerotic lesions,66 and it has been suggested that 5-LO may mediate specific stages of atherosclerosis.67 However, the role of 5-LO in diabetic vascular disease is not yet known. Overall, available evidence suggests that the LOs can contribute to the pathology of atherosclerosis and diabetic vascular disease by virtue of their capacity to oxidize LDL, to induce growth and inflammatory events, and by being in an atherogenic gene locus. The relative importance of the different LOs in this regard is not yet clear. Because the 12/15-LO pathway can be upregulated by hyperglycemia, growth factors, and cytokines, it is likely that it can augment diabetic atherosclerosis and vice versa, thereby setting off a vicious loop of events.
HG culture enhanced 12/15-LO pathway activation and expression in VSMC39 and endothelial cells.42 Furthermore, AII-induced 12/15-LO activity in VSMC was greater in HG relative to normal glucose.39 Apart from AII, 12/15-LO activity and expression in VSMC could also be potently upregulated by platelet-derived growth factor (PDGF) BB and by cytokines such as IL-1, IL-4, and IL-8 in VSMC.68,69 The 15-LO expression was induced in monocytes and endothelial cells by IL-4 or IL-13.41,70–72 Thus, 12/15-LO in vascular and mononuclear cells can be induced by diabetic conditions, growth factors, and cytokines, and may contribute to their biological and atherogenic effects.
The LO pathway may therefore play a role in the cardiovascular complications associated with diabetes. Endothelial cells and VSMC cultured under hyperglycemic conditions produced increased amounts of HETEs.39,42,73 Furthermore, HG-induced adhesion of monocytes to endothelial cells could be mediated by the LO pathway.42,74 The 12/15-LO products also appear to mediate minimally modified LDL-induced monocyte binding to endothelial cells.75 LO products have potent chemotactic and hypertrophic effects in VSMC.76–78 The hypertrophic effects of 12(S)-HETE in VSMC were markedly enhanced under HG culture conditions in a manner similar to those of angiotensin II.77 There is now considerable evidence to support a role for 12/15-LO in promoting the development of diabetes and atherosclerosis. Bleich et al noted that 12/15-LO–deficient mice were resistant to the development of diabetes.79 In vivo relevance of 12/15-LO in human diabetes was suggested by a study demonstrating increased urinary excretion of 12(S)-HETE in diabetic subjects compared with matched nondiabetic controls.80 Interestingly, these diabetic subjects also had decreased urinary prostacyclin levels, suggesting a potential shunting into the 12/15-LO pathway. Recently, increased 12/15-LO expression was noted in a swine model of hyperlipidemia and diabetes-induced accelerated atherosclerosis.60 Diabetes and hyperlipidemia alone increased both monocyte oxidant stress and 12/15-LO expression in arteries, but the combination of these 2 risk factors in this swine model led to not only a marked acceleration of atherosclerosis but also a synergistic increase in oxidant stress and 12/15-LO activation.60 A recent report demonstrated increased expression of 12/15-LO in urine and endothelial cells from diabetic db/db mice.81 Interestingly, it was noted that the increased production of 12/15-LO products by the endothelial cells of the db/db mice was responsible for the observed increased in binding of monocytes to the endothelial cells from db/db versus those from control mice, and it was concluded that the 12/15-LO pathway is important for mediating early vascular changes and inflammatory reactions in diabetes.81 Taken together, these results suggest an in vivo role for leukocyte type 12/15-LO in diabetic atherosclerosis.
Emerging evidence supports a clear role of insulin resistance and diabetes in leading to accelerated cardiovascular disease. As discussed, elevated glucose and diabetes increase the expression and activity of 12/15-LO. However, fewer reports have evaluated the role of 12/15-LO in metabolic disturbances seen in the insulin resistance syndrome. Of interest are studies showing that masoprocol, a LO inhibitor, can reduce triglycerides, free fatty acids, and improve insulin action in both fructose-fed and fat-fed rat models of insulin resistance and type 2 diabetes.82,83 In addition, 12-LO products can downregulate glucose transport in VSMC.84 To further evaluate the effect of insulin resistance on vascular injury responses and 12/15-LO expression, we studied the effect of carotid balloon injury in lean and obese insulin-resistant Zucker rats. After injury, the intima-to-media ratio of obese Zucker rats was significantly greater than leans starting at 14 days after injury and persisting up to at least day 30. The expression of inflammatory mediators including 12/15-LO and IL-6 were markedly increased in obese compared with lean animals suggesting that vascular injury in obese Zucker rats is associated with inflammation. Increased macrophage and p-selectin staining was also seen. These studies (unpublished) indicate an exaggerated injury response in the insulin resistant obese Zucker rat model and that inflammation may play a major role in mediating neointimal growth under these conditions. In addition, 12/15-LO was one of the few genes upregulated in the pancreatic beta cell of the insulin resistant prediabetic Zucker diabetic fatty rat,85 thereby suggesting that 12/15-LO expression is enhanced in the prediabetic metabolic syndrome condition before frank hyperglycemia. Thus 12/15-LO may have a role in the excess cardiovascular disease seen even before diabetes is diagnosed. Because hyperglycemia alone also increases 12/15-LO expression in vascular cells, it is likely that 12/15-LO can participate in the development of type 2 diabetes and atherosclerosis, whereas the associated hyperglycemia, dyslipidemia, and insulin resistance can further augment 12/15-LO pathway activation to set off a vicious loop of inflammatory events. Furthermore, factors such as growth factors, cytokines, and advanced glycation end products, all of which are relevant to the pathogenesis of diabetes, can also upregulate the activity and expression of 12/15-LO (Figure 2).
Figure 2. Actions of 12/15-LO in the vessel wall. Induction of 12/15-LO and its products in endothelial cells by factors such as HG and AGEs can lead to oxidant stress, release of chemokines, activation of monocyte integrins, and key endothelial adhesive molecules and thereby lead to endothelial dysfunction, monocyte activation, and adhesion. In VSMC, similarly, 12/15-LO and its products can induce oxidant stress, adhesion molecules, extracellular matrix proteins, release of inflammatory cytokines, and chemokines, thereby leading to VSMC hypertrophy, migration, and inflammatory responses. 12/15-LO in monocyte/macrophages, endothelial cells, and VSMC can mediate LDL oxidation to oxidized LDL.
Lipoxygenase Products Have Growth, Chemotactic, Adhesive, and Inflammatory Effects in VSMC and Endothelial Cells
Treatment of human aortic endothelial cells with 12(S)-HETE, but not 12(R)-HETE, increased monocyte binding to the endothelial cells, a key early step in the development of atherosclerosis.74 Furthermore, the 12/15-LO ribozyme blocked high-glucose–induced binding of monocytes to endothelial cells, suggesting that glucose-induced LO activation in endothelial cells may lead to endothelial activation and dysfunction.42 The 12(S)-HETE increased the expression of CS-1 fibronectin on endothelial cells, which could be a key mechanism for inducing monocyte adhesion. Certain LO products also increased the surface expression of key inflammatory adhesion molecules such as VCAM-1 via activation of the transcription factor, NF-B.86,87 LO products also directly increased migration, cellular hypertrophy, and fibronectin synthesis in VSMC.76–78 Angiotensin II (AII)-induced increases in total cellular protein content of porcine VSMC were significantly attenuated by a specific LO inhibitor.77 Furthermore, direct addition of the 12-LO product, 12(S)-HETE, increased total cell protein content and fibronectin levels to nearly the same extent as AII.77,78 A rat 12/15-LO ribozyme could significantly inhibit HG-induced fibronectin production.61 Because AII and HG culture can increase the formation of LO products, it is attractive to speculate that the enhanced growth-promoting and matrix effects of the LO products formed by AII and HG are potential mechanisms for the accelerated growth of VSMC and enhanced hypertrophic effects of AII under HG conditions. In support of this, it was noted that rat VSMC and cardiac fibroblasts stably expressing mouse 12/15-LO showed increased growth properties.78,88 In addition, pharmacological LO inhibitors, as well as the 12/15-LO ribozyme, could also significantly inhibit PDGF-induced migration of VSMC.42,68 Because PDGF can upregulate 12/15-LO,68 LO activation may mediate, at least in part, the chemotactic effects of PDGF.
LO products also have proinflammatory effects in VSMC. Thus the 12/15-LO product of linoleic acid, 13-HPODE, led to a significant increase in the activation of the redox-sensitive and inflammatory transcription factor, NF-B in VSMC.87 This was associated with increased transcription of the inflammatory adhesion molecule VCAM-1 and the potent chemokines monocyte chemoattractant protein-1 via an NF-B–dependent mechanism.87,89
Signal Transduction and Gene Regulation Mechanisms by Which LO Products Mediate Their Cellular Actions
HETEs can activate certain isoforms of protein kinase C directly or indirectly by incorporating into membrane phospholipids, which then generate HETE-containing diacylglycerol species to activate protein kinase C.90 They can also activate several mitogen activated protein kinases (MAPKs) and thereby activate key transcription factors that mediate the expression of growth and inflammatory genes.78,90 In VSMC, 12(S)-HETE could lead to the transcription of the fibronectin gene, and this was regulated by the transcription factor CREB in a p38MAPK-dependent manner.78 However, the hydroperoxy LO product, 13(S)-HPODE, could increase the expression of VCAM-1 in an NF-B–dependent manner and partly via p38MAPK.87 Thus these oxidized lipids can serve as novel signal transducers, regulators, and amplifiers of gene induction by high glucose, growth factor, and cytokine actions. Interestingly, a novel role for HPODE and hydroperoxy precursor as seeding molecules responsible for LDL oxidation by artery wall cells and associated oxidative events related to the pathogenesis of atherosclerosis has been demonstrated.91 In monocytes, 9-hydroxyocatadecadienoic acid and 13-hydroxyocatadecadienoic acid (12/15-LO products of linoleic acid metabolism) induced the expression of the scavenger receptor, CD36, apparently via activation of the nuclear receptor, peroxisome proliferator activator-gamma.92 IL-4–induced 12/15-LO activation was also implicated in this process.93
Coffey et al demonstrated that 12/15-LO can lead to the catalytic consumption of the vasodilator, nitric oxide, and prevent nitric oxide-mediated soluble guanylate cyclase activation.94 This suggests that 12/15-LO may mediate the pathology of vascular diseases such as atherosclerosis, hypertension, and diabetes not only by the bioactivity of their lipid products but also by limiting the availability of nitric oxide in the vessel wall. Reactive oxygen species generated during LO pathway activation95 may mediate growth and inflammatory effects in VSMC and endothelial cells. Conversely, high-glucose induced oxidant stress, and reactive oxygen species in diabetes can lead to the induction of 12/15-LO in VSMC and endothelial cells and promote cellular dysfunction. Recent reports show that VSMC derived from 12/15-LO–/– mice grow slower than those derived from genetic control mice, produce much lesser amounts of superoxide, and have reduced activation of MAPKs,96 whereas endothelial cells derived from these 12/15-LO KO mice display decreased binding to monocytes compared with those from control mice.97 However, new data show that endothelial cells from 12/15-LO transgenic mice reciprocally display enhanced monocyte binding relative to those from control mice.97 Interestingly, these 12/15-LO transgenic mice also developed more atherosclerotic lesions.97 Overall, it appears that 12/15-LO can participate in an inflammatory loop with cytokines and other inflammatory genes to amplify or modulate their cellular responses and thereby accelerate the development of cardiovascular complications in diabetes.
In summary, LO and COX-2 enzymes in vascular, inflammatory, and other cells can form products with pleiotropic physiological and pathological effects. These include vasoactive, growth, adhesive, chemotactic, oxidative, and inflammatory responses, which therefore implicate them in the pathogenesis of diabetic vascular disease such as atherosclerosis and hypertension. Although COX-2–specific inhibitors are now available for clinical use, there are currently no clinically safe, pharmacologically selective, and optimally bioavailable inhibitors of 12/15-LO. Hence, the development of 12/15-LO inhibitors, including novel ribozymes, may lead to new antiinflammatory therapies for diabetic vascular complications.
Acknowledgments
We acknowledge grant support from the National Institutes of Health (PO1 HL55798, RO1 DK55240, RO1 DK065073, and RO1 DK58191) and the Juvenile Diabetes Research Foundation International. We thank Dr Q. Cai for his help with the manuscript.
References
Beckman JA, Craeger MA, Libby P. Diabetes and atherosclerosis. epidemiology, pathophysiology, and management. JAMA. 2002; 287: 2570–2581.
Libby P, Plutzky J. Diabetic macrovascular disease. The glucose paradox? Circulation. 2002; 106: 2760–2763.
Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001; 286: 1195–1200.
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414: 813–820.
Ido Y, Kilo C, Williamson JR. Cytosolic NADH/NAD+, free radicals, and vascular dysfunction in early diabetes mellitus. Diabetologia. 1997; 40 (suppl 2): S115–S117.
Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M. Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003; 112: 1049–1057.
Way KJ, Katai N, King GL. Protein kinase C and the development of diabetic vascular complications. Diabet Med. 2001; 18: 945–959.
Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991; 87: 1643–1648.
Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988; 318: 1315–1321.
Schmidt A, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arteriosclerosis Thromb. 1994; 14: 1521–1528.
Schmidt AM, Hori O, Chen J, Li JF, Crandall J, Zhang J, Cao R, Yan SD, Brett J, and Stern D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1): a potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995; 96: 1395–1403.
Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, Hori O, Stern D, Schmidt AM. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest. 1996; 97: 238–243.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.
Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002; 36: 1331–1336.
Shanmugam N, Reddy MA, Guha M, Natarajan R. High Glucose induced expression of pro-inflammatory cytokine and chemokine genes in monocytic cells. Diabetes. 2003; 52: 1256–1264.
Liscovitch M. Crosstalk among multiple signal-activated phospholipases. Trends Biochem Sci. 1992; 17: 393–399.
Di Marzo V. Arachidonic acid and eicosanoids as targets and effectors in second messenger interactions. Prostaglandins Leukot Essent Fatty Acids. 1995; 53: 239–254.
Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J. 1989; 259: 315–324.
Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002; 82: 131–185.
Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. Advances Immunol. 1996; 62: 167–215.
Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human Monocytes. J Biol Chem. 1990; 265: 16737–16740.
Herschman HR. Prostaglandin Synthase 2. Biochim Biophys Acta. 1996; 1299: 125–140.
Hla T, Ristimaki A, Appleby SB, Barriocanal JG. Cyclooxygenase gene expression in inflammation and angiogenesis. Ann N Y Acad Sci. 1993; 696: 197–204.
Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Ann Rev Pharmacol Toxicol. 1998; 38: 97–120.
Robertson RP. Dominance of cyclooxygenase-2 in the regulation of pancreatic islet prostaglandin synthesis. Diabetes. 1998; 47: 1379–1383.
McDaniel ML, Kwon G, Hill JR, Marshall CA, Corbett JA. Cytokines and nitric oxide in islet inflammation and diabetes. Proc Soc Exp Biol Med. 1996; 211: 24–32.
Tran PO, Gleason CE, Poitout V, Robertson RP. Prostaglandin E (2) mediates inhibition of insulin secretion by interleukin-1beta. J Biol Chem. 1999; 274: 31245–31248.
Kwon G, Corbett JA, Hauser S, Hill JR, Turk J, McDaniel ML. Evidence for involvement of the proteasome complex (26S) and NF-kappaB in IL-1?-induced nitric oxide and prostaglandin production by rat islets and RINm5F cells. Diabetes. 1998; 47: 583–591.
Harris RC, McKanna JA, Akai Y, Jacoban HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994; 94: 2504–2510.
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96: 272–277.
Yamamoto S. Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta. 1992; 1128: 117–131.
Kuhn H, Thiele BJ. The diversity of the lipoxygenase family. Many sequence data but little information on biological significance. FEBS Lett. 1999; 449: 7–11.
Funk CD. The molecular biology of mammalian lipoxygenases and the quest for eicosanoid functions using lipoxygenase-deficient mice. Biochim Biophys Acta. 1996; 1304: 65–84.
Yoshimoto T, Suzuki H, Yamamoto S, Takai T, Yokoyama C, Tanabe T. Cloning and sequence analysis of the cDNA for arachidonate 12-lipoxygenase of porcine leukocytes. Proc Natl Acad Sci U S A. 1990; 87: 2142–2146.
Sigal E. The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol. 1991; 260: L13–L28.
Funk CD, Furci L, FitzGerald. Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase. Proc Natl Acad Sci U S A. 1990; 87: 5638–5642.
Izumi T, Hoshiko S, Radmark O, Samuelsson B. Cloning of the cDNA for human 12-lipoxygenase. Proc Natl Acad Sci U S A. 1990; 87: 7477–7481.
Sigal E, Craik CS, Highland E, Grunberger D, Costello LL, Dixon RA, Nadel JA. Molecular cloning and primary structure of human 15-lipoxygenase. Biochem Biophys Res Commun. 1988; 157: 457–464.
Natarajan R, Gu JL, Rossi J, Gonzales N, Lanting L, Xu L, Nadler J. Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1993; 90: 4947–4951.
Kim JA, Gu JL, Natarajan R, Berliner JA, Nadler JL. A leukocyte type of 12-lipoxygenase is expressed in human vascular and mononuclear cells. Evidence for upregulation by angiotensin II. Arterioscler Thromb Vasc Biol. 1995; 15: 942–948.
Lee YW, Kuhn H, Kaiser S, Hennig B, Daugherty A, Toborek M. Interleukin 4 induces transcription of the 15-lipoxygenase I gene in human endothelial cells. J Lipid Res. 2001; 42: 783–791.
Patricia MK, Natarajan R, Dooley AN, Hernandez F, Gu JL, Berliner JA, Rossi JJ, Nadler JL, Meidell RS, Hedrick CC. Adenoviral delivery of a leukocyte-type 12-lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells. Circ Res. 2001; 88: 659–665.
Watanabe T, Medina JF, Haeggstrom JZ, Radmark O, Samuelsson B. Molecular cloning of a 12-lipoxygenase cDNA from rat brain. Eur J Biochem. 1993; 212: 605–612.
Katoh T, Lakkis FG, Makita N, Badr KF. Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Kidney Int. 1994; 46: 341–349.
Chen XS, Kurre U, Jenkins NA, Copeland NG, Funk CD. cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localizations of murine 12-lipoxygenases. J Biol Chem. 1994; 269: 13979–13987.
Linton MF, Fazio S. Cyclooxygenase-2 and inflammation in atherosclerosis. Curr Opin Pharmacol. 2004; 4: 116–123.
Schonbeck U, Sukhova G, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999; 155: 1281–1291.
Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002; 105: 1816–1823.
Tesfamariam B, Brown ML, Deykin D, Cohen RA. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest. 1990; 85: 929–932.
Cosentino F, Eto M, De Paolis P, van der Loo B, Bachschmid M, Ullrich V, Kouroedov A, Gatt CD, Joch H, Volpe M, Luscher TF. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation. 2003; 107: 1017–1023.
Shanmugam N, Kim YS, Lanting L, Natarajan R. Regulation of cyclooxygenase-2 expression in monocytes by ligation of the receptor for advanced glycation end products. J Biol Chem. 2003; 278: 34834–34844.
Shanmugam N, Gaw-Gonzalo I, Natarajan R. Molecular mechanisms of high glucose-induced COX-2 regulation in monocytes. Diabetes. 2004; 53: 795–802.
Miao F, Gonzalo IG, Lanting L, Natarajan R. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J Biol Chem. 2004; 279: 18091–18097.
Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003; 108: 1070–1077.
Han X, Chen S, Sun Y, Nadler JL, Bleich D. Induction of cyclooxygenase-2 gene in pancreatic beta cells by 12-lipoxygenase pathway product 12-hydroxyeicosatetraenoic acid. Mol Endocrinol. 2002; 16: 2145–2154.
Parthasarathy S, Wieland E, Steinberg D. A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. Proc Natl Acad Sci U S A. 1989; 86: 1046–1050.
Folcik VA, Nivar-Aristy RA, Krajewski LP, Cathcart MK. Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J Clin Invest. 1995; 96: 504–510.
Scheidegger KJ, Butler S, Witztum JL. Angiotensin II increases macrophage-mediated modification of low-density lipoprotein via a lipoxygenase-dependent pathway. J Biol Chem. 1997; 272: 21609–21615.
Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H, Sigal E. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2000; 20: 2100–2105.
Natarajan R, Gerrity RG, Gu JL, Lanting L, Thomas L, Nadler JL. Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model. Diabetologia. 2002; 45: 125–133.
Gu JL, Pei H, Thomas L, Nadler JL, Rossi JJ, Lanting L, Natarajan R. Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries. Circulation. 2001; 103: 1446–1452.
Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999; 103: 1597–1604.
George J, Afek A, Shaish A, Levkovitz H, Bloom N, Cyrus T, Zhao L, Funk CD, Sigal E, Harats D. 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation. 2001; 104: 1646–1650.
Zhao L, Cuff CA, Moss E, Wille U, Cyrus T, Klein EA, Pratico D, Rader DJ, Hunter CA, Pure E, Funk CD. Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol Chem. 2002; 277: 35350–35356.
Mehrabian M, Allayee H, Wong J, Shi W, Wang XP, Shaposhnik Z, Funk CD, Lusis AJ, Shih W. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 2002; 91: 120–126.
Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Hadenicht AJ. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci U S A. 2003; 100: 1238–1243.
Mehrabian M, Allayee H. 5-Lipoxygenase and atherosclerosis. Curr Opin Lipidol. 2003; 14: 447–457.
Natarajan R, Bai W, Rangarajan V, Gonzales N, Gu JL, Lanting L, Nadler JL. Platelet-derived growth factor BB mediated regulation of 12-lipoxygenase in porcine aortic smooth muscle cells. J Cell Physiol. 1996; 169: 391–400.
Natarajan R, Rosdahl J, Gonzales N, Bai W. Regulation of 12-lipoxygenase by cytokines in vascular smooth muscle cells. Hypertension. 1997; 30: 873–879.
Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci U S A. 1992; 89: 217–221.
Nassar GM, Morrow JD, Roberts LJ, 2nd, Lakkis FG, Badr KF. Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. J Biol Chem. 1994; 269: 27631–27634.
Roy B, Cathcart MK. Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of Jak2 and Tyk2 in human monocytes. J Biol Chem. 1998; 273: 32023–32029.
Brown ML, Jakubowski JA, Leventis LL, Deykin D. Elevated glucose alters eicosanoid release from porcine aortic endothelial cells. J Clin Invest. 1988; 82: 2136–2141.
Patricia MK, Kim JA, Harper CM, Shih PT, Berliner JA, Natarajan R, Nadler JL, Hedrick CC. Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 2615–2622.
Honda HM, Leitinger N, Frankel M, Goldhaber JI, Natarajan R, Nadler JL, Weiss JN, Berliner JA. Induction of monocyte binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites. Arterioscler Thromb Vasc Biol. 1999; 19: 680–686.
Nakao J, Ooyama T, Ito H, Chang WC, Murota S. Comparative effect of lipoxygenase products of arachidonic acid on rat aortic smooth muscle cell migration. Atherosclerosis. 1982; 44: 339–342.
Natarajan R, Gonzales N, Lanting L, Nadler J. Role of the lipoxygenase pathway in angiotensin II-induced vascular smooth muscle cell hypertrophy. Hypertension. 1994; 23: I142–I147.
Reddy MA, Thimmalapura PR, Lanting L, Nadler JL, Fatima S, Natarajan R. The oxidized lipid and lipoxygenase product 12(S)-hydroxyeicosatetraenoic acid induces hypertrophy and fibronectin transcription in vascular smooth muscle cells via p38 MAPK and cAMP response element-binding protein activation. Mediation of angiotensin II effects. J Biol Chem. 2002; 277: 9920–9928.
Bleich D, Chen S, Zipser B, Sun D, Funk CD, Nadler JL. Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J Clin Invest. 1999; 103: 1431–1436.
Antonipillai I, Nadler J, Vu EJ, Bughi S, Natarajan R, Horton R. A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease. J Clin Endocrinol Metab. 1996; 81: 1940–1945.
Hatley ME, Srinivasan S, Reilly KB, Bolick DT, Hedrick CC. Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. J Biol Chem. 2003; 278: 25369–25375.
Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Brignetti D, Luo J, Khandwala A, Reaven GM. Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type 2 diabetes. Diabetologia. 1999; 42: 102–106.
Scribner K, Gadbois T, Gowri M, Azhar Sl, Reaven G. Masoprocol decreases serum triglyceride concentration in rats with fructose-induced hypertriglyceridemia. Metabolism. 2000; 9: 1106–1110.
Alpert E, Gruzman A, Totary H, Kaiser N, Reich R, Sasson S. A natural protective mechanism against hyperglycemia in vascular endothelial and smooth muscle cells: role of glucose and 12-hydroxyeicosatetraenoic acid. Biochem J. 2002; 362: 413–422.
Tokuyama Y, Sturis J, DePaoli AM, Takeda J, Stoffel M, Tang J, Sun X, Polonsky KS, Bell GI. Evolution of beta cell dysfunction in the male Zucker diabetic fatty rat. Diabetes. 1995; 44: 1447–1457.
Sultana CY, Shen V, Rattan V, Kalra K. Lipoxygenase metabolites induced expression of adhesion molecules and transendothelial migration of monocyte-like HL-60 cells is linked to protein kinase C activation. J Cell Physiol. 1996; 167: 477–487.
Natarajan R, Reddy MA. Malik KU, Fatima S, Khan BV. Signaling mechanisms of nuclear factor-kappab-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21: 1408–1413.
Wen Y, Gu J, Peng X, Zhang G, Nadler JL. Overexpression of 12-lipoxygenase and cardiac fibroblast hypertrophy. Trends in Cardiovasc Med. 2003; 134: 129–136.
Dwarakanath RS, Sahar S, Reddy MA, Castanotto D, Rossi JJ, Natarajan R. Regulation of monocyte chemoattractant protein-1 by the oxidized lipid,13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kB). Mol Cell Cardiol. 2004; 36: 585–595.
Natarajan R, Nadler JL. Lipoxygenases and Lipid Signaling in Diabetes. Frontiers in Biosciences. 2003; 8: S783–S795.
Navab M, Hama SY, Cooke CJ, Anantharamaiah GM, Chaddha M, Jin L, Subbanagounder G, Faull KF, Reddy ST, Miller NE, Fogelman AM. Normal high-density lipoprotein inhibits three steps in the formation of mildly oxidized low-density lipoprotein: step 1. J Lipid Res. 2000; 41: 1481–1494.
Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998; 93: 241–252.
Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of PPAR- ligands in macrophages by 12/15-lipoxygenase. Nature. 1999; 400: 378–382.
Coffey MJ, Natarajan R, Chumley PH, Coles B, Thimmalapura PR, Nowell M, Kuhn H, Lewis MJ, Freeman BA, O’Donnell VB. Catalytic consumption of nitric oxide by 12/15- lipoxygenase: inhibition of monocyte soluble guanylate cyclase activation. Proc Natl Acad Sci U S A. 2001; 98: 8006–8011.
Roy P, Roy SK, Mitra A, Kulkarni AP. Superoxide generation by lipoxygenase in the presence of NADH and NADPH. Biochim Biophys Acta. 1994; 1214: 171–179.
Reddy MA, Kim YS, Lanting L, Natarajan R. Reduced growth factor responses in vascular smooth muscle cells derived from 12/15-lipoxygenase deficient mice. Hypertension. 2003; 41: 1294–1300.
Reilly KB, Srinivasan S, Hatley ME, Kim Patricia M, Lannigan J, Bolick DT, Vandenhoff G, Pei H, Natarajan R, Nadler JL, Hedrick CC. 12/15 lipoxygenase activity mediates inflammatory monocyte: endothelial interactions and atherosclerosis in vivo. J Biol Chem. 2003; 279: 9440–9450.(Rama Natarajan; Jerry L. )