ATVB In Focus
http://www.100md.com
《动脉硬化血栓血管生物学》
From the Division of Cardiology, Emory University, Atlanta, GA 30322
Correspondence to Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB 1639 Pierce Dr., Atlanta, GA 30322. E-mail kgriend@emory.edu
Much interest has been generated recently concerning the role of reactive oxygen species (ROS) in vascular health and disease. The original "oxidative modification hypothesis of atherosclerosis" put forth in the early 1980’s by Steinberg and colleagues suggested that oxidative modification of LDL enhanced its atherogenic properties. An explosion of articles in this area substantiated the role of oxidized LDL in atherosclerosis (reviewed by Chisolm and Steinberg1), but recent work has expanded this hypothesis to include a role for free radicals in hypertension,2 the processes leading to restenosis after balloon angioplasty,3 vascular inflammation,4 diabetic vascular disease,5 and angiogenesis.6 Perhaps more importantly, ROS are essential to the normal functioning of the vessel wall, including endothelium-dependent relaxation, contraction, and the smooth muscle cell and endothelial cell growth and survival involved in repair and remodeling of the vessel wall. These diverse and critical roles of ROS in vascular physiology and pathophysiology make understanding the sources of ROS generation of vital importance in the design of therapeutic interventions.
See page 274
Traditionally, macrophages have been assumed to be the source of most of the ROS in the vessel wall. There is no doubt that these cells are powerful ROS generators and that they play an important role in vessel pathology. However, it has become clear that virtually all cells in the vessel wall produce ROS, in varying amounts and in response to diverse stimuli. Endothelial cells, smooth muscle cells, and adventitial cells all produce ROS, which can then act in an autocrine or paracrine fashion to modulate cellular function.7 A classic example of this is the inactivation of nitric oxide by superoxide. Superoxide generated by all three cell types can react with NO, thus impairing endothelium-dependent vasodilation.8–10
Not only are there different cellular sources of ROS, but also cells use different enzymes to produce and scavenge ROS in different circumstances. Ultimately, it is the balance of pro-oxidant and antioxidant enzyme activity that dictates both intracellular and extracellular ROS levels. In the vasculature, three isoforms of superoxide dismutase (SOD), including extracellular SOD, Cu/Zn SOD, and the mitochondrial-restricted MnSOD; catalase; glutathione peroxidase, and thio- and peroxi-redoxins, are mainly responsible for removal of ROS. The enzymes that mediate ROS production vary with the physiological or pathophysiological environment or stimulus. Attention has mainly focused on NAD(P)H oxidases, xanthine oxidase, myeloperoxidase, uncoupled endothelial nitric oxide synthase (eNOS), cyclooxygenases, and mitochondria. Thus, mitochondrial-derived ROS are intimately involved in the response to ischemia-reperfusion,11 whereas NAD(P)H oxidases and uncoupled eNOS have been shown to be important in hypertension.12,13 Both NAD(P)H oxidases and xanthine oxidases appear to play a role in atherosclerosis,14 and myeloperoxidase has been shown to be associated with endothelial dysfunction and the risk of cardiovascular events in patients with coronary artery disease.15,16 To further complicate matters, ROS produced by one enzyme system often activates a more potent ROS-producing system, as is the case for NAD(P)H oxidase-mediated activation of xanthine oxidase in response to shear stress of endothelial cells,17 or NAD(P)H oxidase-mediated uncoupling of eNOS in hypertension.13
Finally, the identity of the ROS produced can have profound effects on the final physiological response. One of the major consequences of superoxide production is inactivation of nitric oxide, thus limiting relaxation in normal vessels and impairing relaxation in diseased arteries.18 Hypochlorous acid derived from myeloperoxidase also inhibits endothelial function, but by a different mechanism.19 In contrast, H2O2 and other peroxides appear to be more important in regulating growth-related signaling in vascular smooth muscle cells and inflammatory responses in vascular lesions.20 Thus, currently available antioxidants that target only superoxide might not be expected to impact lesion development, whereas scavenging of H2O2 would be expected to be more efficacious.
Given the complexity of ROS-generating systems and cellular antioxidant defenses, as well as their clear relevance to vascular biology and disease, this issue of Atherosclerosis, Thrombosis, and Vascular Biology begins a series of Brief Reviews that addresses sources and scavenging of ROS in blood vessels. Each review will highlight one of the important sources of ROS or antioxidant enzymes in the vessel wall, and will attempt to provide a perspective on its role in vascular physiology. In this issue is the first of these articles, "Redox mechanisms in blood vessels" by Mueller et al, which provides an integration of many of the concepts discussed above and presents a framework for understanding the relationship among these various oxidative and reductive systems. This series as a whole will thus provide a state-of-the-art update on vascular ROS production and it role in cardiovascular physiology and disease.
References
Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000; 28: 1815–1826.
Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension. 2004; 44: 248–252.
Hanna IR, Taniyama Y, Szocs K, Rocic P, Griendling KK. NAD(P)H oxidase-derived reactive oxygen species as mediators of angiotensin II signaling. Antioxid Redox Signal. 2002; 4: 899–914.
Aslan M, Freeman BA. Oxidases and oxygenases in regulation of vascular nitric oxide signaling and inflammatory responses. Immunol Res. 2002; 26: 107–118.
Endemann DH, Schiffrin EL. Nitric oxide, oxidative excess, and vascular complications of diabetes mellitus. Curr Hypertens Rep. 2004; 6: 85–89.
Maulik N, Das DK. Redox signaling in vascular angiogenesis. Free Radic Biol Med. 2002; 33: 1047–1060.
Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.
Wang HD, Hope S, Du Y, Quinn MT, Cayatte A, Pagano PJ, Cohen RA. Paracrine role of adventitial superoxide anion in mediating spontaneous tone of the isolated rat aorta in angiotensin II-induced hypertension. Hypertension. 1999; 33: 1225–1232.
Somers MJ, Mavromatis K, Galis ZS, Harrison DG. Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation. 2000; 101: 1722–1728.
Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996; 97: 1916–1923.
Chakraborti T, Das S, Mondal M, Roychoudhury S, Chakraborti S. Oxidant, mitochondria and calcium: an overview. Cell Signal. 1999; 11: 77–85.
Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension. 2002; 40: 511–515.
Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003; 111: 1201–1209.
Spiekermann S, Landmesser U, Dikalov S, Bredt M, Gamez G, Tatge H, Reepschlager N, Hornig B, Drexler H, Harrison DG. Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation. 2003; 107: 1383–1389.
Vita JA, Brennan ML, Gokce N, Mann SA, Goormastic M, Shishehbor MH, Penn MS, Keaney JF, Jr., Hazen SL. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation. 2004; 110: 1134–1139.
Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003; 349: 1595–1604.
McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, Jo H, Harrison DG. Role of xanthine oxidoreductase and the NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol. 2003; 85: H2290–H2297.
Harrison DG. Endothelial function and oxidant stress. Clin Cardiol. 1997; 20: II-11–II-17.
Stocker R, Huang A, Jeranian E, Hou JY, Wu TT, Thomas SR, Keaney JF, Jr. Hypochlorous acid impairs endothelium-derived nitric oxide bioactivity through a superoxide-dependent mechanism. Arterioscler Thromb Vasc Biol. 2004; 24: 2028–2033.
Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation. 2003; 108: 2034–2040.(Kathy K. Griendling)
Correspondence to Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB 1639 Pierce Dr., Atlanta, GA 30322. E-mail kgriend@emory.edu
Much interest has been generated recently concerning the role of reactive oxygen species (ROS) in vascular health and disease. The original "oxidative modification hypothesis of atherosclerosis" put forth in the early 1980’s by Steinberg and colleagues suggested that oxidative modification of LDL enhanced its atherogenic properties. An explosion of articles in this area substantiated the role of oxidized LDL in atherosclerosis (reviewed by Chisolm and Steinberg1), but recent work has expanded this hypothesis to include a role for free radicals in hypertension,2 the processes leading to restenosis after balloon angioplasty,3 vascular inflammation,4 diabetic vascular disease,5 and angiogenesis.6 Perhaps more importantly, ROS are essential to the normal functioning of the vessel wall, including endothelium-dependent relaxation, contraction, and the smooth muscle cell and endothelial cell growth and survival involved in repair and remodeling of the vessel wall. These diverse and critical roles of ROS in vascular physiology and pathophysiology make understanding the sources of ROS generation of vital importance in the design of therapeutic interventions.
See page 274
Traditionally, macrophages have been assumed to be the source of most of the ROS in the vessel wall. There is no doubt that these cells are powerful ROS generators and that they play an important role in vessel pathology. However, it has become clear that virtually all cells in the vessel wall produce ROS, in varying amounts and in response to diverse stimuli. Endothelial cells, smooth muscle cells, and adventitial cells all produce ROS, which can then act in an autocrine or paracrine fashion to modulate cellular function.7 A classic example of this is the inactivation of nitric oxide by superoxide. Superoxide generated by all three cell types can react with NO, thus impairing endothelium-dependent vasodilation.8–10
Not only are there different cellular sources of ROS, but also cells use different enzymes to produce and scavenge ROS in different circumstances. Ultimately, it is the balance of pro-oxidant and antioxidant enzyme activity that dictates both intracellular and extracellular ROS levels. In the vasculature, three isoforms of superoxide dismutase (SOD), including extracellular SOD, Cu/Zn SOD, and the mitochondrial-restricted MnSOD; catalase; glutathione peroxidase, and thio- and peroxi-redoxins, are mainly responsible for removal of ROS. The enzymes that mediate ROS production vary with the physiological or pathophysiological environment or stimulus. Attention has mainly focused on NAD(P)H oxidases, xanthine oxidase, myeloperoxidase, uncoupled endothelial nitric oxide synthase (eNOS), cyclooxygenases, and mitochondria. Thus, mitochondrial-derived ROS are intimately involved in the response to ischemia-reperfusion,11 whereas NAD(P)H oxidases and uncoupled eNOS have been shown to be important in hypertension.12,13 Both NAD(P)H oxidases and xanthine oxidases appear to play a role in atherosclerosis,14 and myeloperoxidase has been shown to be associated with endothelial dysfunction and the risk of cardiovascular events in patients with coronary artery disease.15,16 To further complicate matters, ROS produced by one enzyme system often activates a more potent ROS-producing system, as is the case for NAD(P)H oxidase-mediated activation of xanthine oxidase in response to shear stress of endothelial cells,17 or NAD(P)H oxidase-mediated uncoupling of eNOS in hypertension.13
Finally, the identity of the ROS produced can have profound effects on the final physiological response. One of the major consequences of superoxide production is inactivation of nitric oxide, thus limiting relaxation in normal vessels and impairing relaxation in diseased arteries.18 Hypochlorous acid derived from myeloperoxidase also inhibits endothelial function, but by a different mechanism.19 In contrast, H2O2 and other peroxides appear to be more important in regulating growth-related signaling in vascular smooth muscle cells and inflammatory responses in vascular lesions.20 Thus, currently available antioxidants that target only superoxide might not be expected to impact lesion development, whereas scavenging of H2O2 would be expected to be more efficacious.
Given the complexity of ROS-generating systems and cellular antioxidant defenses, as well as their clear relevance to vascular biology and disease, this issue of Atherosclerosis, Thrombosis, and Vascular Biology begins a series of Brief Reviews that addresses sources and scavenging of ROS in blood vessels. Each review will highlight one of the important sources of ROS or antioxidant enzymes in the vessel wall, and will attempt to provide a perspective on its role in vascular physiology. In this issue is the first of these articles, "Redox mechanisms in blood vessels" by Mueller et al, which provides an integration of many of the concepts discussed above and presents a framework for understanding the relationship among these various oxidative and reductive systems. This series as a whole will thus provide a state-of-the-art update on vascular ROS production and it role in cardiovascular physiology and disease.
References
Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000; 28: 1815–1826.
Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension. 2004; 44: 248–252.
Hanna IR, Taniyama Y, Szocs K, Rocic P, Griendling KK. NAD(P)H oxidase-derived reactive oxygen species as mediators of angiotensin II signaling. Antioxid Redox Signal. 2002; 4: 899–914.
Aslan M, Freeman BA. Oxidases and oxygenases in regulation of vascular nitric oxide signaling and inflammatory responses. Immunol Res. 2002; 26: 107–118.
Endemann DH, Schiffrin EL. Nitric oxide, oxidative excess, and vascular complications of diabetes mellitus. Curr Hypertens Rep. 2004; 6: 85–89.
Maulik N, Das DK. Redox signaling in vascular angiogenesis. Free Radic Biol Med. 2002; 33: 1047–1060.
Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000; 86: 494–501.
Wang HD, Hope S, Du Y, Quinn MT, Cayatte A, Pagano PJ, Cohen RA. Paracrine role of adventitial superoxide anion in mediating spontaneous tone of the isolated rat aorta in angiotensin II-induced hypertension. Hypertension. 1999; 33: 1225–1232.
Somers MJ, Mavromatis K, Galis ZS, Harrison DG. Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation. 2000; 101: 1722–1728.
Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996; 97: 1916–1923.
Chakraborti T, Das S, Mondal M, Roychoudhury S, Chakraborti S. Oxidant, mitochondria and calcium: an overview. Cell Signal. 1999; 11: 77–85.
Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo H, Holland SM, Harrison DG. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension. 2002; 40: 511–515.
Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003; 111: 1201–1209.
Spiekermann S, Landmesser U, Dikalov S, Bredt M, Gamez G, Tatge H, Reepschlager N, Hornig B, Drexler H, Harrison DG. Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation. 2003; 107: 1383–1389.
Vita JA, Brennan ML, Gokce N, Mann SA, Goormastic M, Shishehbor MH, Penn MS, Keaney JF, Jr., Hazen SL. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation. 2004; 110: 1134–1139.
Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003; 349: 1595–1604.
McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, Jo H, Harrison DG. Role of xanthine oxidoreductase and the NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol. 2003; 85: H2290–H2297.
Harrison DG. Endothelial function and oxidant stress. Clin Cardiol. 1997; 20: II-11–II-17.
Stocker R, Huang A, Jeranian E, Hou JY, Wu TT, Thomas SR, Keaney JF, Jr. Hypochlorous acid impairs endothelium-derived nitric oxide bioactivity through a superoxide-dependent mechanism. Arterioscler Thromb Vasc Biol. 2004; 24: 2028–2033.
Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation. 2003; 108: 2034–2040.(Kathy K. Griendling)