CD40 Ligand
http://www.100md.com
动脉硬化血栓血管生物学 2005年第6期
From the Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
Correspondence to Pascal J. Goldschmidt-Clermont, Division of Cardiology, Department of Medicine, Duke University Medical Center, DUMC 3703, Durham, NC 27710. E-mail Golds017@mc.duke.edu
Key Words: atherosclerosis • inflammation • CD40 ligand • stem cells • endothelial progenitor cells
Atherosclerosis is a chronic inflammatory process that affects arteries selectively and results from imbalance between injury and repair. The complex etiology of atherosclerosis has proved formidable, indeed.1,2 Although linked to the presence of microorganisms, the atherosclerotic inflammation does not seem to result from infection; specifically, not the type of infection that can be treated with adequate antibiotics.3,4 Infections can nevertheless promote atherosclerotic inflammation indirectly by augmenting the release of cytokines in the bloodstream, such that local arterial intimal lesions can be affected.5 Furthermore, some antiinflammatory drugs like COX-2 inhibitors appear to worsen the risk of patients for cardiac events, rather than antagonize atherosclerotic inflammation and its thromboembolic consequences.6,7 Hence, the development of vascular specific antiinflammatory therapies is limited by the necessity of a basal inflammatory response to maintain arterial homeostasis by constitutive arterial repair involving both local and distant processes, such as the production of vascular precursor cells by the bone marrow. There is an exquisite need for selective antiinflammatory drugs, drugs that do not alter the limited form of inflammation required for arterial repair signaling but do control the unchecked inflammation that occurs in patients who are unable, for a variety of reasons, to mount a successful repair response.
See page 1244
In such context, the dyad of CD40 and its extracellular ligand (CD40L, also called CD154) appears an ideal target for more specific antiatherosclerotic therapies. The proinflammatory dyad (CD40/CD40L) is expressed on the surface of endothelial and smooth muscle cells, macrophages, lymphocytes, megakaryocytes, and platelets—all progeny of bone marrow stem cells—and the cellular constituents of advanced atherosclerotic lesions. The CD40/CD40L system is considered an important mediator of atherosclerogenesis, because inhibition of CD40 signaling by specific antibodies in the low density lipoprotein receptor knockout mouse model (ldlr–/–) fed a high fat diet reduces de novo plaque formation, plaque area, and accumulation of smooth muscle cells, macrophages, and lipid.8,9 Blocking the CD40/CD40L dyad may also stabilize plaques, thus rendering them less vulnerable to rupture, and hence, lessening the risk for coronary and other arterial thrombotic events.10 Thus, antibodies that block CD40L binding stabilize atherosclerotic plaques against rupture in the ApoE–/– mouse fed a high fat diet.10 Consistent with a role in plaque destabilization, CD40L was also shown to represent an important link between thrombosis and inflammation, as platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo, suggesting that platelets and CD40L are not only involved in thrombosis, but that they also directly initiate an inflammatory response of the vessel wall.11
Consequently, it is of no surprise that CD40/CD40L is a marker of adverse cardiovascular events; serum levels of soluble fully activated CD40L are higher in individuals with unstable angina,12 predict high-risk atherosclerotic lesions,13 and identify women at risk for cardiovascular events.14 Instructively, heritable syndromes in man that eliminate CD40L are lethal in the first or second decades of life.15,16 Yet it logically was anticipated that the site of action of the dyad-blocking antibodies would be CD40/CD40L moieties expressed on the surface of inflammatory cells of hematopoietic origin.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bavendiek and colleagues took on the challenge of demonstrating that the cells that carry the proatherosclerogenic contribution of the CD40/CD40L dyad are of hematopoietic-derived lineages and originate from the bone marrow.17 Binding of CD40L to the CD40 receptor on the surface of endothelial cells, smooth muscle cells, or macrophages triggers the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, adhesion molecules, and procoagulants, all of which elaborate the inflammatory response. Yet the critical cellular source of CD40L within the atherogenic context is not known. Instructively, CD40L overexpression is not unique to atherosclerotic inflammation, as many diseases of chronic inflammation, including type 1 and type 2 diabetes, lupus nephritis, multiple sclerosis, and inflammatory bowel diseases, are characterized by high levels of CD40L found either within the inflamed tissue or systemically.
In the present study, the authors tested 2 hypotheses. First, that systemic removal of CD40L by genetic knockout would slow the progression of atherosclerosis, consistent with the antibody blocking experiments. They compared double mutant ldlr–/–/cd40l–/– mice fed a high fat diet to ldlr–/–mice fed a high fat diet, and showed that, indeed, atherosclerosis was reduced and plaque morphology appeared more stable in the absence of CD40L expression. But a surprise was in store for the second hypothesis, that the bone marrow–derived hematopoietic stem cells are the vital source of atherosclerogenic CD40L. Specifically, whole bone marrow cells were isolated from either ldlr–/–mice or ldlr–/–/cd40l–/–mice and used to reconstitute bone marrow in irradiated ldlr–/–recipient mice. Given that systemic elimination of CD40L by mutation reduced atherosclerosis in the ldlr–/–mice, one would have predicted that the irradiated mice receiving ldlr–/–/cd40l–/– bone marrow would develop less atherosclerosis compared with those receiving ldlr–/–bone marrow, but this was not the case. Instead, the authors report that the atherosclerotic lesions in both groups of recipient mice were indistinguishable, although both were reduced in size in response to bone marrow reconstitution, as previously described.18
Why did elimination of CD40L, from the very cells that compose the atherosclerotic plaques and are believed to mediate atherosclerotic inflammation, not work locally to reduce disease progression? The lack of effect of restoring CD40L expression by cells originating from the bone marrow could be interpreted as evidence that CD40L expression is critical for progression and destabilization of atherosclerotic plaque when expressed by cells that are not of bone marrow origin (ie, not derived from hematopoietic stem cells). According to this interpretation, the idea that the CD40L that contributes to atherosclerotic inflammation originates from hematopoietic stem cells would not be supported by these data.
Hematopoietic stem cells of the bone marrow give rise to 2 types of progenitors, the myeloid progenitors that become monocytes, neutrophils, eosinophils, basophils, megakaryocytes, and erythrocytes, and the lymphoid progenitors that colonize the thymus and give rise to lymphocytes. At sites of injury, monocytes differentiate into macrophages under the influence of tissue-derived chemokines and cytokines. Endothelial cells and smooth muscles cells of injured arteries are continually replaced through division of progenitor cells, derived either locally or from circulating precursors originally from the bone marrow, that engraft on the arterial surface.19,20 The last few years has seen the emergence of a paradigm where a finite reservoir of bone marrow stem cells becomes depleted or dysfunctional, such that it fails to produce endothelial progenitor cells (and perhaps other vascular progenitors) competent for arterial repair, either as a result of the slow aging process, or even more rapidly as a result of aging in the presence of major risk factors for atherosclerosis.21,22 Thus, intravenous infusion of bone marrow progenitor from wild-type mice and young, but not old, ApoE–/– mice significantly attenuated atherosclerosis and suppressed interleukin-6 expression in the blood, a critical proinflammatory cytokine.
Hence, another intriguing possibility is that CD40L does not solely promote atherosclerosis when expressed on the surface of bone marrow progenitors, but instead may also contribute to arterial repair by facilitating interaction of repair competent bone marrow cells with the damaged arterial wall. Thus, restoring CD40L expression on bone marrow–derived cells via transplant might lead to two competing effects: (1) promotion of inflammation in arterial plaques via immune competent cells, and (2) improvement of arterial repair via competent bone marrow–derived vascular progenitors that use CD40/CD40L to somehow restore arterial integrity. This latter effect may dominate such that the net result of restoring CD40L expression in bone marrow–derived cells is the absence of detectable worsening of atherosclerotic lesions in ldlr–/– mice fed a high-fat diet.
In conclusion, any successful therapy for atherosclerosis will be one that achieves balance between three essential features: it must (1) limit arterial injury, (2) control unchecked inflammation in response to arterial injury, but (3) not disrupt bone marrow–derived cell–mediated arterial repair. The intriguing study of Bavendiek et al proves once again that mediators of disease processes can also, when expressed at lower levels, contribute to fundamental aspects of tissue homeostasis.
Acknowledgments
This work was supported by grants from the National Institutes of Health (AG023073-01A1, HL71536-08, and HL73042) to P.J.G.-C., and by grants from the National Institutes of Health (AG023073-01A1S1) and a Howard Hughes Medical Institute Medical Research Fellowship to O.A.A.
References
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105: 1135–1143.
Shishehbor MH, Bhatt DL. Inflammation and atherosclerosis. Current Atherosclerosis Reports. 2004; 6: 131–139.
Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005; 352: 1646–1654.
Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005; 352: 1637–1645.
Hansson GK. Inflammation, atherosclerosis, & coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286: 954–959.
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005; 352: 1092–1102.
Mach F, Schönbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998; 394: 200–203.
Schönbeck U, Sukhove GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.
Lutgens E, Cleutjens KB, Heeneman S, Koteliansky BE, Burkly LC, and Daemen MJ. Both early and delayed anti-CD40 antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7476–7469.
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.
Aukrust P, Muller F, Ueland T, Berget T, Aaeser E, Brunsvig A, Solum NO, Forfang K, Froland SS, Gullestad L. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation. 1999; 100: 614–620.
Blake GJ, Ostfeld RJ, Yucel EK, Varo N, Schönbeck U, Blake MA, Gerhard M, Ridker PM, Libby P, Lee RT. Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma. Arterioscler Thromb Vasc Biol. 2003; 23: e11–e14.
Schönbeck U, Varo N, Libby P, Buring M, PR. Soluble CD40L and cardiovascular risk in women. Circulation. 2001; 104: 2266–2268.
Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M, et al. The CD40ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993; 72: 291–300.
Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedel MA, Edelhoff S, Disteche CM, Simoneaux DK, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993; 259: 990–993.
Bavendiek U, Zirlik A, LaClair S, MacFarlane L, Libby P, Schönbeck U. Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells. Arterioscler Thromb Vasc Biol. 2005; 25: 1244–1249.
Schiller NK, Kubo N, Boisvert WA, Curtiss LK. Effect of gamma-irradiation and bone marrow transplantation on atherosclerosis in LDLreceptor deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 1674–1680.
Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in apoE-deficient mice. J Clin Invest. 2004; 113: 1258–1265.
Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation. 2002; 106: 1199–1204.
Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003; 108: 457–463.
Goldschmidt-Clermont PJ. Loss of bone marrow–derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J. 2003; 146: S5–S12.(Olujimi A. Ajijola; Pasca)
Correspondence to Pascal J. Goldschmidt-Clermont, Division of Cardiology, Department of Medicine, Duke University Medical Center, DUMC 3703, Durham, NC 27710. E-mail Golds017@mc.duke.edu
Key Words: atherosclerosis • inflammation • CD40 ligand • stem cells • endothelial progenitor cells
Atherosclerosis is a chronic inflammatory process that affects arteries selectively and results from imbalance between injury and repair. The complex etiology of atherosclerosis has proved formidable, indeed.1,2 Although linked to the presence of microorganisms, the atherosclerotic inflammation does not seem to result from infection; specifically, not the type of infection that can be treated with adequate antibiotics.3,4 Infections can nevertheless promote atherosclerotic inflammation indirectly by augmenting the release of cytokines in the bloodstream, such that local arterial intimal lesions can be affected.5 Furthermore, some antiinflammatory drugs like COX-2 inhibitors appear to worsen the risk of patients for cardiac events, rather than antagonize atherosclerotic inflammation and its thromboembolic consequences.6,7 Hence, the development of vascular specific antiinflammatory therapies is limited by the necessity of a basal inflammatory response to maintain arterial homeostasis by constitutive arterial repair involving both local and distant processes, such as the production of vascular precursor cells by the bone marrow. There is an exquisite need for selective antiinflammatory drugs, drugs that do not alter the limited form of inflammation required for arterial repair signaling but do control the unchecked inflammation that occurs in patients who are unable, for a variety of reasons, to mount a successful repair response.
See page 1244
In such context, the dyad of CD40 and its extracellular ligand (CD40L, also called CD154) appears an ideal target for more specific antiatherosclerotic therapies. The proinflammatory dyad (CD40/CD40L) is expressed on the surface of endothelial and smooth muscle cells, macrophages, lymphocytes, megakaryocytes, and platelets—all progeny of bone marrow stem cells—and the cellular constituents of advanced atherosclerotic lesions. The CD40/CD40L system is considered an important mediator of atherosclerogenesis, because inhibition of CD40 signaling by specific antibodies in the low density lipoprotein receptor knockout mouse model (ldlr–/–) fed a high fat diet reduces de novo plaque formation, plaque area, and accumulation of smooth muscle cells, macrophages, and lipid.8,9 Blocking the CD40/CD40L dyad may also stabilize plaques, thus rendering them less vulnerable to rupture, and hence, lessening the risk for coronary and other arterial thrombotic events.10 Thus, antibodies that block CD40L binding stabilize atherosclerotic plaques against rupture in the ApoE–/– mouse fed a high fat diet.10 Consistent with a role in plaque destabilization, CD40L was also shown to represent an important link between thrombosis and inflammation, as platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo, suggesting that platelets and CD40L are not only involved in thrombosis, but that they also directly initiate an inflammatory response of the vessel wall.11
Consequently, it is of no surprise that CD40/CD40L is a marker of adverse cardiovascular events; serum levels of soluble fully activated CD40L are higher in individuals with unstable angina,12 predict high-risk atherosclerotic lesions,13 and identify women at risk for cardiovascular events.14 Instructively, heritable syndromes in man that eliminate CD40L are lethal in the first or second decades of life.15,16 Yet it logically was anticipated that the site of action of the dyad-blocking antibodies would be CD40/CD40L moieties expressed on the surface of inflammatory cells of hematopoietic origin.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bavendiek and colleagues took on the challenge of demonstrating that the cells that carry the proatherosclerogenic contribution of the CD40/CD40L dyad are of hematopoietic-derived lineages and originate from the bone marrow.17 Binding of CD40L to the CD40 receptor on the surface of endothelial cells, smooth muscle cells, or macrophages triggers the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, adhesion molecules, and procoagulants, all of which elaborate the inflammatory response. Yet the critical cellular source of CD40L within the atherogenic context is not known. Instructively, CD40L overexpression is not unique to atherosclerotic inflammation, as many diseases of chronic inflammation, including type 1 and type 2 diabetes, lupus nephritis, multiple sclerosis, and inflammatory bowel diseases, are characterized by high levels of CD40L found either within the inflamed tissue or systemically.
In the present study, the authors tested 2 hypotheses. First, that systemic removal of CD40L by genetic knockout would slow the progression of atherosclerosis, consistent with the antibody blocking experiments. They compared double mutant ldlr–/–/cd40l–/– mice fed a high fat diet to ldlr–/–mice fed a high fat diet, and showed that, indeed, atherosclerosis was reduced and plaque morphology appeared more stable in the absence of CD40L expression. But a surprise was in store for the second hypothesis, that the bone marrow–derived hematopoietic stem cells are the vital source of atherosclerogenic CD40L. Specifically, whole bone marrow cells were isolated from either ldlr–/–mice or ldlr–/–/cd40l–/–mice and used to reconstitute bone marrow in irradiated ldlr–/–recipient mice. Given that systemic elimination of CD40L by mutation reduced atherosclerosis in the ldlr–/–mice, one would have predicted that the irradiated mice receiving ldlr–/–/cd40l–/– bone marrow would develop less atherosclerosis compared with those receiving ldlr–/–bone marrow, but this was not the case. Instead, the authors report that the atherosclerotic lesions in both groups of recipient mice were indistinguishable, although both were reduced in size in response to bone marrow reconstitution, as previously described.18
Why did elimination of CD40L, from the very cells that compose the atherosclerotic plaques and are believed to mediate atherosclerotic inflammation, not work locally to reduce disease progression? The lack of effect of restoring CD40L expression by cells originating from the bone marrow could be interpreted as evidence that CD40L expression is critical for progression and destabilization of atherosclerotic plaque when expressed by cells that are not of bone marrow origin (ie, not derived from hematopoietic stem cells). According to this interpretation, the idea that the CD40L that contributes to atherosclerotic inflammation originates from hematopoietic stem cells would not be supported by these data.
Hematopoietic stem cells of the bone marrow give rise to 2 types of progenitors, the myeloid progenitors that become monocytes, neutrophils, eosinophils, basophils, megakaryocytes, and erythrocytes, and the lymphoid progenitors that colonize the thymus and give rise to lymphocytes. At sites of injury, monocytes differentiate into macrophages under the influence of tissue-derived chemokines and cytokines. Endothelial cells and smooth muscles cells of injured arteries are continually replaced through division of progenitor cells, derived either locally or from circulating precursors originally from the bone marrow, that engraft on the arterial surface.19,20 The last few years has seen the emergence of a paradigm where a finite reservoir of bone marrow stem cells becomes depleted or dysfunctional, such that it fails to produce endothelial progenitor cells (and perhaps other vascular progenitors) competent for arterial repair, either as a result of the slow aging process, or even more rapidly as a result of aging in the presence of major risk factors for atherosclerosis.21,22 Thus, intravenous infusion of bone marrow progenitor from wild-type mice and young, but not old, ApoE–/– mice significantly attenuated atherosclerosis and suppressed interleukin-6 expression in the blood, a critical proinflammatory cytokine.
Hence, another intriguing possibility is that CD40L does not solely promote atherosclerosis when expressed on the surface of bone marrow progenitors, but instead may also contribute to arterial repair by facilitating interaction of repair competent bone marrow cells with the damaged arterial wall. Thus, restoring CD40L expression on bone marrow–derived cells via transplant might lead to two competing effects: (1) promotion of inflammation in arterial plaques via immune competent cells, and (2) improvement of arterial repair via competent bone marrow–derived vascular progenitors that use CD40/CD40L to somehow restore arterial integrity. This latter effect may dominate such that the net result of restoring CD40L expression in bone marrow–derived cells is the absence of detectable worsening of atherosclerotic lesions in ldlr–/– mice fed a high-fat diet.
In conclusion, any successful therapy for atherosclerosis will be one that achieves balance between three essential features: it must (1) limit arterial injury, (2) control unchecked inflammation in response to arterial injury, but (3) not disrupt bone marrow–derived cell–mediated arterial repair. The intriguing study of Bavendiek et al proves once again that mediators of disease processes can also, when expressed at lower levels, contribute to fundamental aspects of tissue homeostasis.
Acknowledgments
This work was supported by grants from the National Institutes of Health (AG023073-01A1, HL71536-08, and HL73042) to P.J.G.-C., and by grants from the National Institutes of Health (AG023073-01A1S1) and a Howard Hughes Medical Institute Medical Research Fellowship to O.A.A.
References
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105: 1135–1143.
Shishehbor MH, Bhatt DL. Inflammation and atherosclerosis. Current Atherosclerosis Reports. 2004; 6: 131–139.
Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005; 352: 1646–1654.
Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C; ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005; 352: 1637–1645.
Hansson GK. Inflammation, atherosclerosis, & coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286: 954–959.
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005; 352: 1092–1102.
Mach F, Schönbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998; 394: 200–203.
Schönbeck U, Sukhove GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.
Lutgens E, Cleutjens KB, Heeneman S, Koteliansky BE, Burkly LC, and Daemen MJ. Both early and delayed anti-CD40 antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7476–7469.
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.
Aukrust P, Muller F, Ueland T, Berget T, Aaeser E, Brunsvig A, Solum NO, Forfang K, Froland SS, Gullestad L. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation. 1999; 100: 614–620.
Blake GJ, Ostfeld RJ, Yucel EK, Varo N, Schönbeck U, Blake MA, Gerhard M, Ridker PM, Libby P, Lee RT. Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma. Arterioscler Thromb Vasc Biol. 2003; 23: e11–e14.
Schönbeck U, Varo N, Libby P, Buring M, PR. Soluble CD40L and cardiovascular risk in women. Circulation. 2001; 104: 2266–2268.
Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M, et al. The CD40ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993; 72: 291–300.
Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedel MA, Edelhoff S, Disteche CM, Simoneaux DK, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993; 259: 990–993.
Bavendiek U, Zirlik A, LaClair S, MacFarlane L, Libby P, Schönbeck U. Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells. Arterioscler Thromb Vasc Biol. 2005; 25: 1244–1249.
Schiller NK, Kubo N, Boisvert WA, Curtiss LK. Effect of gamma-irradiation and bone marrow transplantation on atherosclerosis in LDLreceptor deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 1674–1680.
Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in apoE-deficient mice. J Clin Invest. 2004; 113: 1258–1265.
Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation. 2002; 106: 1199–1204.
Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, Pippen AM, Annex BH, Dong C, Taylor DA. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003; 108: 457–463.
Goldschmidt-Clermont PJ. Loss of bone marrow–derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J. 2003; 146: S5–S12.(Olujimi A. Ajijola; Pasca)