VEGF: is it just an inducer of heme oxygenase-1 expression?
Inflammatory reactions are often associated with hemolysis and consequently with the accumulation of free heme released from oxidized hemoglobin. This results in internalization of the free heme by vascular endothelial cells (ECs), where the iron in the core of the heme structure acts as a potent pro-oxidant to promote EC cytotoxicity.1 The only manner in which ECs can decrease the intracellular levels of free heme is to up-regulate the expression heme oxygenase-1 (HO-1), a stress-responsive enzyme that catalyzes the initial and rate-limiting steps in the oxidative degradation of heme into biliverdin, iron, and carbon monoxide (CO).|, http://www.100md.com
We and others have previously shown that the expression of HO-1 prevents the deleterious effects associated with vascular injury, such as the development of arteriosclerotic lesions that arise following EC injury/denudation.2,3 This protective effect is mimicked by exogenous CO, thus suggesting that it is mediated via the ability of HO-1 to convert heme into CO.3 An interesting feature in the protective effect of CO is that a single "pulse" of exogenous CO (one hour) seems to be sufficient to block the development of arteriosclerotic lesions, such as those that arise following balloon injury of the carotid artery in rats.3 This suggests that CO triggers a protective response in cells of the vascular wall that continues to act despite the fact that exposure of these cells to CO has been discontinued. The molecular mechanism underlying this potent and long-lasting protective effect remains to be established.
The article by Bussolati and colleagues that appears in this issue of Blood (page 761) may help to further explain the mechanism underlying the protective effect of HO-1 and CO. The authors demonstrate that vascular endothelial growth factor (VEGF) induces the expression of HO-1 in ECs and, perhaps more important, that HO-1 enzymatic activity in these cells can be critical for the angiogenic effect of VEGF. This adds significantly to the previous observation that HO-1 promotes angiogenesis,4 in that it directly links the potent angiogenic effect of VEGF to the expression and enzymatic activity of HO-1. In addition, the data obtained by the authors may provide important answers related to the mechanism of action of VEGF in terms of modulating arteriosclerotic lesions triggered by EC injury/denudation. Based on these findings, it is likely that the salutary effects of VEGF are largely due to the expression of HO-1. Induction of HO-1 would not only enhance re-endothelialization of the injured vessels, but it would also protect the newly formed ECs from undergoing apoptosis, suppress the proinflammatory phenotype associated with monocyte/macrophage (M{phi} ) activation, and inhibit smooth muscle cell proliferation, all of which are key features in the development of arteriosclerotic lesions (reviewed in Soares et al5).
It is interesting to note that expression of VEGF and HO-1 in ECs may trigger a "positive feedback loop" in which VEGF up-regulates HO-1 and HO-1 up-regulates VEGF.6 A similar phenomenon has been shown to mediate the anti-inflammatory effect of interleukin-10 (IL-10) in M{phi} , in which IL-10 up-regulates HO-17 and HO-1 up-regulates IL-10.8 These types of positive feedback loops may explain why a single pulse of exogenous CO, given before vascular injury, is sufficient without further treatment to block the development of arteriosclerotic lesions.3 This may also explain the potent and long-lasting protective effects of HO-1 and/or CO in a variety of other inflammatory situations.'y.#*, http://www.100md.com
--- Miguel P. Soares'y.#*, http://www.100md.com
Beth Israel Deaconess Medical Center and Instituto Gubenkian de Ciência'y.#*, http://www.100md.com
References'y.#*, http://www.100md.com
Balla J, Jacob HS, Balla G, Nath K, Eaton JW, Vercellotti GM. Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. Proc Natl Acad Sci U S A. 1993;90: 9285-9289. [Abstract]
Duckers HJ, Boehm M, True AL, et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001;7: 693-698. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 2003;9: 183-190. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Deramaudt BM, Braunstein S, Remy P, Abraham NG. Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. J Cell Biochem. 1998;68: 121-127. 3.0.CO;2-K&link_type=DOI">[CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003;24: 449-455. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Jozkowicz A, Huk I, Nigisch A, Weigel G, Weidinger F, Dulak J. Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1. Antioxidants Redox Signaling. 2002;4: 577-585. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med. 2002;8: 240-246. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Otterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6: 422-428. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Related Articles in Blood Online :/a6x[rx, 百拇医药
Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration./a6x[rx, 百拇医药
Benedetta Bussolati, Asif Ahmed, Helen Pemberton, R. Clive Landis, Francesco Di Carlo, Dorian O. Haskard, and Justin C. Mason Blood 2004 103: 761-766. [Abstract] [Full Text]
We and others have previously shown that the expression of HO-1 prevents the deleterious effects associated with vascular injury, such as the development of arteriosclerotic lesions that arise following EC injury/denudation.2,3 This protective effect is mimicked by exogenous CO, thus suggesting that it is mediated via the ability of HO-1 to convert heme into CO.3 An interesting feature in the protective effect of CO is that a single "pulse" of exogenous CO (one hour) seems to be sufficient to block the development of arteriosclerotic lesions, such as those that arise following balloon injury of the carotid artery in rats.3 This suggests that CO triggers a protective response in cells of the vascular wall that continues to act despite the fact that exposure of these cells to CO has been discontinued. The molecular mechanism underlying this potent and long-lasting protective effect remains to be established.
The article by Bussolati and colleagues that appears in this issue of Blood (page 761) may help to further explain the mechanism underlying the protective effect of HO-1 and CO. The authors demonstrate that vascular endothelial growth factor (VEGF) induces the expression of HO-1 in ECs and, perhaps more important, that HO-1 enzymatic activity in these cells can be critical for the angiogenic effect of VEGF. This adds significantly to the previous observation that HO-1 promotes angiogenesis,4 in that it directly links the potent angiogenic effect of VEGF to the expression and enzymatic activity of HO-1. In addition, the data obtained by the authors may provide important answers related to the mechanism of action of VEGF in terms of modulating arteriosclerotic lesions triggered by EC injury/denudation. Based on these findings, it is likely that the salutary effects of VEGF are largely due to the expression of HO-1. Induction of HO-1 would not only enhance re-endothelialization of the injured vessels, but it would also protect the newly formed ECs from undergoing apoptosis, suppress the proinflammatory phenotype associated with monocyte/macrophage (M{phi} ) activation, and inhibit smooth muscle cell proliferation, all of which are key features in the development of arteriosclerotic lesions (reviewed in Soares et al5).
It is interesting to note that expression of VEGF and HO-1 in ECs may trigger a "positive feedback loop" in which VEGF up-regulates HO-1 and HO-1 up-regulates VEGF.6 A similar phenomenon has been shown to mediate the anti-inflammatory effect of interleukin-10 (IL-10) in M{phi} , in which IL-10 up-regulates HO-17 and HO-1 up-regulates IL-10.8 These types of positive feedback loops may explain why a single pulse of exogenous CO, given before vascular injury, is sufficient without further treatment to block the development of arteriosclerotic lesions.3 This may also explain the potent and long-lasting protective effects of HO-1 and/or CO in a variety of other inflammatory situations.'y.#*, http://www.100md.com
--- Miguel P. Soares'y.#*, http://www.100md.com
Beth Israel Deaconess Medical Center and Instituto Gubenkian de Ciência'y.#*, http://www.100md.com
References'y.#*, http://www.100md.com
Balla J, Jacob HS, Balla G, Nath K, Eaton JW, Vercellotti GM. Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. Proc Natl Acad Sci U S A. 1993;90: 9285-9289. [Abstract]
Duckers HJ, Boehm M, True AL, et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001;7: 693-698. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 2003;9: 183-190. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Deramaudt BM, Braunstein S, Remy P, Abraham NG. Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. J Cell Biochem. 1998;68: 121-127. 3.0.CO;2-K&link_type=DOI">[CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003;24: 449-455. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Jozkowicz A, Huk I, Nigisch A, Weigel G, Weidinger F, Dulak J. Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1. Antioxidants Redox Signaling. 2002;4: 577-585. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med. 2002;8: 240-246. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Otterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6: 422-428. [CrossRef][Medline] [Order article via Infotrieve]/a6x[rx, 百拇医药
Related Articles in Blood Online :/a6x[rx, 百拇医药
Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration./a6x[rx, 百拇医药
Benedetta Bussolati, Asif Ahmed, Helen Pemberton, R. Clive Landis, Francesco Di Carlo, Dorian O. Haskard, and Justin C. Mason Blood 2004 103: 761-766. [Abstract] [Full Text]