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Endothelial dysfunction and inflammation: What is the link?

2003; Elsevier BV; Volume: 63; Linguagem: Inglês

10.1046/j.1523-1755.63.s84.12.x

1523-1755

Jan Galle, Thomas Quaschning, Stefan Seibold, Christoph Wanner,

Cardiovascular Health and Disease Prevention

Endothelial dysfunction and inflammation: What is the link? Cardiovascular disease, resulting from arteriosclerotic remodeling of the vasculature, is the main cause of death in end-stage renal disease (ESRD) patients. Early during the course of arteriosclerosis, endothelial dysfunction can be detected in various vascular beds, including peripheral forearm arteries, as well as the coronary circulation. Furthermore, endothelial dysfunction seems to predict the prognosis of cardiovascular disease. Therefore, the question deserves attention whether endothelial dysfunction is simply a marker of cardiovascular disease, or an active player in the progress of the disease. A possible link between arteriosclerosis, endothelial dysfunction, and cardiovascular disease is increased oxidative stress. Inflammatory processes involved in the pathogenesis of arteriosclerosis enhance vascular O2¯ formation, leading to endothelial dysfunction. An activated renin angiotensin system, together with oxidized low-density lipoprotein, may play a prominent role for enhanced vascular oxidative stress. In this context, the endothelium is not only a target of oxygen radicals, but may also contribute to O2¯ formation. It is the aim of this article to highlight the interplay of inflammation, endothelial dysfunction, and oxidative stress. Endothelial dysfunction and inflammation: What is the link? Cardiovascular disease, resulting from arteriosclerotic remodeling of the vasculature, is the main cause of death in end-stage renal disease (ESRD) patients. Early during the course of arteriosclerosis, endothelial dysfunction can be detected in various vascular beds, including peripheral forearm arteries, as well as the coronary circulation. Furthermore, endothelial dysfunction seems to predict the prognosis of cardiovascular disease. Therefore, the question deserves attention whether endothelial dysfunction is simply a marker of cardiovascular disease, or an active player in the progress of the disease. A possible link between arteriosclerosis, endothelial dysfunction, and cardiovascular disease is increased oxidative stress. Inflammatory processes involved in the pathogenesis of arteriosclerosis enhance vascular O2¯ formation, leading to endothelial dysfunction. An activated renin angiotensin system, together with oxidized low-density lipoprotein, may play a prominent role for enhanced vascular oxidative stress. In this context, the endothelium is not only a target of oxygen radicals, but may also contribute to O2¯ formation. It is the aim of this article to highlight the interplay of inflammation, endothelial dysfunction, and oxidative stress. Doubtlessly, one of the major achievements in medicine during the last two decades has been the discovery that the vascular endothelium is not simply a semipermeable membrane, but instead forms a most active organ with endocrine and paracrine functions1.Inagami T. Naruse M. Hoover R. Endothelium as an endocrine organ.Ann Rev Physiol. 1995; 57: 171-189Crossref PubMed Scopus (149) Google Scholar. Concerning cardiovascular medicine, most relevant functions of the endothelium are the release of relaxing factors, contractile factors, and of antiaggregatory substances. Prominent representatives of relaxing factors are nitric oxide (NO) and prostacycline (PGI2), both of which also have antiaggregatory properties on platelets. Endothelium-derived hyperpolarizing factor (EDHF) is another vasodilator released from the endothelium. Endothelin-1 (ET-1) and thromboxane (TXA2) are the best-characterized endothelial contractile factors so far. Endothelial function, with its relevance to cardiovascular medicine, has frequently been reviewed2.Ignarro L.J. Physiology and pathophysiology of nitric oxide.Kidney Int. 1996; 49: S2-S5Google Scholar. Arteriosclerotic cardiovascular disease is the main cause of death in patients with ESRD3.Foley R.N. Parfrey P.S. Sarnak M.J. Epidemiology of cardiovascular disease in chronic renal disease.J Am Soc Nephrol. 1998; 9: S16-S23Crossref PubMed Scopus (33) Google Scholar. Arteriosclerosis is considered to be an inflammatory disease associated with enhanced oxygen radical formation4.Ross R. Mechanisms of disease. Atherosclerosis: An inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (19199) Google Scholar,5.Lusis A.J. Atherosclerosis.Nat. 2000; 407: 233-241Crossref Scopus (4668) Google Scholar; enhanced oxidative stress is likely to be a major cause for endothelial dysfunction. It is the aim of this article to highlight the interplay of inflammation, endothelial dysfunction, and oxidative stress. Particular emphasis is placed on the role of angiotensin II (AngII) and atherogenic lipoproteins. Endothelial dysfunction is a sensitive indicator for cardiovascular disease6.Anderson T.J. Uehata A. Gerhard M.D. et al.Close relation of endothelial function in the human coronary and peripheral circulations.J Am Coll Cardiol. 1995; 26: 1235-1241Abstract Full Text PDF PubMed Scopus (1759) Google Scholar, predicts its prognosis7.Suwaidi J.A. Hamasaki S. Higano S.T. et al.Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.Circulation. 2000; 101: 948-954Crossref PubMed Scopus (1836) Google Scholar, and is closely associated with the development of arteriosclerosis8.Hashimoto M. Eto M. Akishita M. et al.Correlation between flow-mediated vasodilatation of the brachial artery and intima-media thickness in the carotid artery in men.Arterioscler Thromb Vasc Biol. 1999; 19: 2795-2800Crossref PubMed Scopus (141) Google Scholar. The term endothelial dysfunction could, of course, implicate a "loss of function" of any of the numerous activities of the endothelium. In the context of vascular diseases, however, endothelial dysfunction usually describes reduced dilatory capacities, particularly reduced NO activity. Probably the most important mechanism leading to reduced NO activity is enhanced oxygen radical formation. Superoxide anion (O2−) scavenges NO, yielding peroxynitrite (ONOO-), which is rather stable but can rearrange to form nitrate and the highly reactive OH·9.Halliwell B. Zhao K. Whiteman M. Nitric oxide and peroxynitrite. The ugly, the uglier and the not so good: A personal view of recent controversies.Free Radic Res. 1999; 31: 651-669Crossref PubMed Scopus (266) Google Scholar. Many studies clearly indicate that endothelial dysfunction is closely correlated with arteriosclerosis, and that O2− formation is enhanced in hypercholesterolemia and arteriosclerosis10.Ohara Y. Peterson T.E. Harrison D.G. Hypercholesterolemia increases endothelial superoxide anion production.J Clin Invest. 1993; 91: 2546-2551Crossref PubMed Scopus (1647) Google Scholar. Indeed, endothelial dysfunction can be detected (e.g., by means of reduced forearm blood flow, early in the development of arteriosclerosis, and in patients with hypercholesterolemia)11.Zeiher A.M. Drexler H. Wollschlager H. Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis.Circulation. 1991; 84: 1984-1992Crossref PubMed Scopus (467) Google Scholar. Importantly, endothelial dysfunction occurs in arteries without visible characteristics of arteriosclerotic lesions such as fatty streaks or plaque formation. In view of the numerous endocrine and paracrine functions of the endothelium, the question deserves attention whether endothelial dysfunction is simply a sensitive indicator for cardiovascular disease, or whether it is an active player in its pathophysiology. To shed some light on these questions, the development of arteriosclerosis shall briefly be summarized. Arteriosclerosis, a generic term for several diseases in which the arterial wall becomes thickened and loses elasticity, is not a static condition; rather, it reflects a continuous development over decades from macroscopically intact arteries to grossly damaged and ruptured sclerotic plaques, with different stages being present simultaneously within one individual. Important steps during atherogenesis include enhanced endothelial permeability, expression of adhesion molecules, monocyte adhesion and immigration, foam cell formation, fatty streaks, smooth muscle cell migration, plaque formation, and finally plaque rupture and thrombus formation. Earlier concepts on the pathophysiology of arteriosclerosis were based on the assumption of an initial injury leading to intimal lesions, and subsequent repair mechanisms ("response to injury" hypothesis)12.Ross R. Glomset J.A. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis.Science. 1973; 180: 1332-1339Crossref PubMed Scopus (1053) Google Scholar. Today we know that even in macroscopically intact arteries, processes take place that can be best defined as chronically inflammatory4.Ross R. Mechanisms of disease. Atherosclerosis: An inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (19199) Google Scholar. Arguments that support the hypothesis of a chronic inflammation in arteriosclerosis include the following: Cells found in early atherosclerotic lesions are typically inflammatory cells (monocytes/macrophages and T-lymphocytes); early in arteriosclerosis, enhanced vascular oxygen radical formation can be detected, as well as enhanced activity of lipoxygenases; arteriosclerosis is associated with enhanced serum levels of inflammation parameters; the arteriosclerotic artery produces different hydrolytic enzymes, adhesion molecules, cytokines, and growth factors, as seen in chronic inflammation. In addition, large clinical studies clearly show a strong correlation between markers of inflammation and clinical outcome in patients with coronary heart disease. In particular, high sensitive C-reactive protein (hs-CRP) has been identified as a predictor for cardiovascular events in patients with and without known coronary heart disease13.Ridker P.M. Cushman M. Stampfer M.J. et al.Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.N Engl J Med. 1997; 336: 973-979Crossref PubMed Scopus (4891) Google Scholar,14.Harb T.S. Zareba W. Moss A.J. et al.Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction.Am J Cardiol. 2002; 89: 216-221Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar. As mentioned above, at very early stages of arteriosclerosis (characterized by enhanced endothelial permeability, expression of adhesion molecules, monocyte adhesion, and immigration), endothelial dysfunction can be detected. For example, in one study, the intima-media thickness and plaque formation of the common carotid artery of 34 men with arteriosclerosis was correlated with flow mediated dilation (FMD) of the brachial artery. A significant negative correlation of FMD with the intima-media thickness of the common carotid artery was found, supporting the concept that endothelial dysfunction is significantly related to atherogenesis8.Hashimoto M. Eto M. Akishita M. et al.Correlation between flow-mediated vasodilatation of the brachial artery and intima-media thickness in the carotid artery in men.Arterioscler Thromb Vasc Biol. 1999; 19: 2795-2800Crossref PubMed Scopus (141) Google Scholar. In another study, a close relation between coronary artery endothelium-dependent vasomotor responses to acetylcholine and FMD in the brachial artery was found6.Anderson T.J. Uehata A. Gerhard M.D. et al.Close relation of endothelial function in the human coronary and peripheral circulations.J Am Coll Cardiol. 1995; 26: 1235-1241Abstract Full Text PDF PubMed Scopus (1759) Google Scholar. The relevance of endothelial dysfunction for the prognosis of patients was shown in a study of the Mayo Clinic: coronary endothelial dysfunction is a strong predictor for future cardiovascular events in patients with coronary heart disease7.Suwaidi J.A. Hamasaki S. Higano S.T. et al.Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.Circulation. 2000; 101: 948-954Crossref PubMed Scopus (1836) Google Scholar. Thus, there is strong evidence that arteriosclerosis is an inflammatory disease, and that endothelial dysfunction is an early event in this process. How could inflammation contribute to endothelial dysfunction, and how could the endothelium contribute to inflammation? Certainly, many different factors may contribute to the state of inflammation in the vasculature, as summarized in Figure 1. For patients with ESRD, it makes sense to distinguish between endogenous and exogenous factors, because the dialysis treatment, in addition to uremia, may be a source for continuous exposure to pro-inflammatory stimuli. What these different factors have in common is that they all—albeit by different mechanisms—enhance oxidative stress. Endothelial dysfunction through scavenging of NO by O2− is one important consequence of enhanced oxidative stress, as outlined above. In various vascular or renal diseases, enhanced formation of reactive oxygen species is considered to be pathogenic (e.g., in atherosclerosis, glomerular diseases, renal failure, pyelonephritis, or aminoglycoside nephropathy)15.Klahr S. Oxygen radicals and renal diseases.Miner Electrolyte Metab. 1997; 23: 140-143PubMed Google Scholar,16.Gwinner W. Landmesser U. Brandes R.P. et al.Reactive oxygen species and antioxidant defense in puromycin aminonucleoside glomerulopathy.J Am Soc Nephrol. 1997; 8: 1722-1731PubMed Google Scholar. Furthermore, oxidative stress importantly influences vascular cell cycle decisions; induction of apoptosis17.Galle J. Schneider R. Heinloth A. et al.Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: Role of oxidative stress.Kidney Int. 1999; 55: 1450-1461Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar,18.Dimmeler S. Haendeler J. Galle J. Zeiher A.M. Oxidized low density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases: A mechanistic clue to the "response to injury" hypothesis.Circulation. 1997; 95: 1760-1763Crossref PubMed Scopus (335) Google Scholar, as well as induction of cell proliferation19.Heinloth A. Heermeier K. Raff U. et al.Stimulation of NADPH oxidase by oxidized LDL induces proliferation of human vascular endothelial cells.J Am Soc Nephrol. 2000; 11: 1819-1825Crossref PubMed Google Scholar, has been described. The scope of this article would be disrupted if all the influences listed in Figure 1 which contribute to inflammation and oxidative stress should be discussed in detail. Instead, we will focus on two factors, AngII and oxidized low density lipoprotein (OxLDL), for two reasons: First, AngII and OxLDL are well characterized as potentially endothelium-damaging agents, and, second, we possess pharmacologic tools to interfere with their activity. Accumulation of OxLDL in atherosclerotic plaques is a well-known event in the development of atherosclerosis20.Ylä-Herttuala S. Palinski W. Butler S.W. et al.Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL.Arterioscler Thromb. 1994; 14: 32-40Crossref PubMed Google Scholar. Only recently did it become apparent that atherosclerotic arteries (human atherectomy preparations and arteries of hypercholesterolemic monkeys) show enrichment with AngII, co-localizing with resident macrophages21.Potter D.D. Sobey C.G. Tompkins P.K. et al.Evidence that macrophages in atherosclerotic lesions contain angiotensin II.Circulation. 1998; 98: 800-807Crossref PubMed Google Scholar. Thus, AngII accumulates in the same vascular region as OxLDL. Not only do AngII and OxLDL co-localize in atherosclerotic plaques, there is strong experimental evidence that these agents interact with each other, with relevance for vascular biology and atherosclerosis. Clinical studies suggest that ACE-inhibitors are of particular benefit for endothelial function in hypercholesterolemic patients with high LDL levels22.Mancini G.B.J. Henry G.C. Macaya C. et al.Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: The TREND (Trial on Reversing ENdothelial Dysfunction) study.Circulation. 1996; 94: 258-265Crossref PubMed Scopus (1068) Google Scholar,23.Cashin Hemphill L. Holmvang G. Chan R.C. et al.Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: No answer yet. QUIET Investigators. QUinapril Ischemic Event Trial.Am J Cardiol. 1999; 83: 43-47Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar. Furthermore, several studies have shown that the expression of the OxLDL receptor LOX-1, and of the AT1 receptor, is stimulated by the respective other receptor agonist24.Nickenig G. Sachinidis A. Michaelsen F. et al.Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells.Circulation. 1997; 95: 473-478Crossref PubMed Scopus (244) Google Scholar,25.Morawietz H. Rueckschloss U. Niemann B. et al.Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low density lipoprotein.Circulation. 1999; 100: 899-902Crossref PubMed Scopus (234) Google Scholar. In cultured smooth muscle cells, LDL induced expression of the AT1 receptor24.Nickenig G. Sachinidis A. Michaelsen F. et al.Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells.Circulation. 1997; 95: 473-478Crossref PubMed Scopus (244) Google Scholar. Thus, LDL may sensitize the vascular tissue to AngII. On the other hand, expression of the OxLDL receptor LOX-1 and uptake of OxLDL in human umbilical vein endothelial cells (HUVEC) is increased by AngII25.Morawietz H. Rueckschloss U. Niemann B. et al.Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low density lipoprotein.Circulation. 1999; 100: 899-902Crossref PubMed Scopus (234) Google Scholar. Together, these studies imply that AngII and OxLDL amplify the effect of the respective other agonist. But how could AngII and OxLDL contribute to arteriosclerosis, inflammation, and endothelial dysfunction? Recently, it has become apparent that AngII is a potent stimulator of vascular oxygen radical production, thereby contributing to endothelial dysfunction and inflammation26.Griendling K.K. Minieri C.A. Ollerenshaw J.D. Alexander R.W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.Circ Res. 1994; 74: 1141-1148Crossref PubMed Scopus (2384) Google Scholar,27.Sohn H-Y. Raff U. Hoffmann A. et al.Differential role of Angiotensin II receptor subtypes on endothelial O2− formation.Br J Pharmacol. 2000; 131: 667-672Crossref PubMed Scopus (88) Google Scholar. Cell culture studies with rat smooth muscle cell preparations provided first experimental evidence for stimulation of O2− formation by AngII26.Griendling K.K. Minieri C.A. Ollerenshaw J.D. Alexander R.W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.Circ Res. 1994; 74: 1141-1148Crossref PubMed Scopus (2384) Google Scholar. In experiments with rat smooth muscle cell membranes, AngII-induced stimulation of O2− formation could be inhibited by diphenylene iodinium, suggesting that O2− was produced by membrane-bound NAD(P)H oxidases26.Griendling K.K. Minieri C.A. Ollerenshaw J.D. Alexander R.W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.Circ Res. 1994; 74: 1141-1148Crossref PubMed Scopus (2384) Google Scholar. In the mean time, it has been shown that AngII also induces O2− formation in endothelial cells and nonvascular tissue28.Hannken T. Schroeder R. Zahner G. et al.Reactive oxygen species stimulate p44/42 mitogen-activated protein kinase and induce p27Kip1: Role in angiotensin II-mediated hypertrophy of proximal tubular cells.J Am Soc Nephrol. 2000; 11: 1387-1397Crossref PubMed Google Scholar. In numerous studies, it has been demonstrated that AngII stimulates vascular NAD(P)H oxidase-dependent O2− formation via the AT1-receptor. The NAD(P)H oxidase consists of four major subunits: a plasma membrane spanning cytochrome b558 (composed of the large subunit gp91phox and the small subunit p22phox), and 2 cytosolic components, p47phox and p67phox29.Griendling K.K. Sorescu D. Ushio-Fukai M. NAD(P)H oxidase: Role in cardiovascular biology and disease.Circ Res. 2000; 86: 494-501Crossref PubMed Scopus (2604) Google Scholar. In smooth muscle cells, the NADPH subunits p22phox, p47phox, and eventually p67phox, are involved in O2− formation29.Griendling K.K. Sorescu D. Ushio-Fukai M. NAD(P)H oxidase: Role in cardiovascular biology and disease.Circ Res. 2000; 86: 494-501Crossref PubMed Scopus (2604) Google Scholar. In endothelial cells, mRNAs for gp91phox, p22phox, p47phox, and p67phox have been detected, and the gp91phox30.Görlach A. Brandes R.P. Nguyen K. et al.A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall.Circ Res. 2000; 87: 26-32Crossref PubMed Scopus (538) Google Scholar and p22phox19.Heinloth A. Heermeier K. Raff U. et al.Stimulation of NADPH oxidase by oxidized LDL induces proliferation of human vascular endothelial cells.J Am Soc Nephrol. 2000; 11: 1819-1825Crossref PubMed Google Scholar subunits seem to be of particular importance for O2− formation in endothelial cells. The particular importance of AngII-induced oxidative stress for vascular biology has been investigated in the context of vasomotor tone and of cell cycle regulation (e.g., enhanced O2− formation resulted in impairment of endothelium-dependent dilations)31.Laursen J.B. Rajagopalan S. Galis Z. et al.Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension.Circulation. 1997; 95: 588-593Crossref PubMed Scopus (755) Google Scholar, which could be prevented by liposome-encapsulated superoxide dismutase. Indirect evidence that AngII-induced O2− formation takes place in vivo in humans was provided by a study using the forearm plethysmography method, which allows direct measurement of AngII-induced vasomotor actions. Constrictor actions of AngII in the human forearm were enhanced during NO inhibition and were attenuated during vitamin C infusion, suggesting AngII-associated stimulation of endothelial NO and of oxygen radicals, respectively32.Dijkhorst-Oei L.T. Stroes E.S.G. Koomans H.A. Rabelink T.J. Acute simultaneous stimulation of nitric oxide and oxygen radicals by angiotensin II in humans in vivo.J Cardiovasc Pharmacol. 1999; 33: 420-424Crossref PubMed Scopus (79) Google Scholar. The impact of AngII on cell cycle decisions via activation of NAD(P)H-dependent oxidases has been demonstrated in vascular and nonvascular tissue, and may be of particular importance for cellular turnover in arteriosclerosis. For example, AngII causes vascular smooth muscle cell hypertrophy, and inhibition of p22phox mRNA expression in vascular smooth muscle cells results in a significant inhibition of AngII-stimulated NADH(P)H-dependent superoxide production, subsequent hydrogen peroxide production, and H3-leucine incorporation33.Ushio Fukai M. Zafari A.M. Fukui T. et al.p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells.J Biol Chem. 1996; 271: 23317-23321Crossref PubMed Scopus (694) Google Scholar. Thus, AngII-induced O2− formation has important consequences for the NO metabolism and for cell cycle decisions, potentially affecting the course of arteriosclerosis. Animal studies with cholesterol-fed rabbits provided first the indirect evidence for a role of LDL in the induction of oxidative stress. Aortas from hypercholesterolemic rabbits produced significantly more superoxide than control aortas10.Ohara Y. Peterson T.E. Harrison D.G. Hypercholesterolemia increases endothelial superoxide anion production.J Clin Invest. 1993; 91: 2546-2551Crossref PubMed Scopus (1647) Google Scholar. Later, our group was able to show directly that incubation of cultured human umbilical vein endothelial cells (HUVEC), and of isolated arteries with oxidized LDL or Lp(a), stimulated O2− formation34.Galle J. Bengen J. Schollmeyer P. Wanner C. Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein(a): Role of oxygen-derived radicals.Circulation. 1995; 92: 1582-1589Crossref PubMed Scopus (133) Google Scholar. Functional consequences of OxLDL-induced oxidative stress extend to atherosclerosis, vasomotor regulation, and endothelial dysfunction. OxLDL affects endothelial function and impairs endothelium-dependent dilations34.Galle J. Bengen J. Schollmeyer P. Wanner C. Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein(a): Role of oxygen-derived radicals.Circulation. 1995; 92: 1582-1589Crossref PubMed Scopus (133) Google Scholar. The impact of OxLDL on apoptotic cell death may be a clue to its role in the development of atherosclerosis. OxLDL induces apoptosis in HUVEC17.Galle J. Schneider R. Heinloth A. et al.Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: Role of oxidative stress.Kidney Int. 1999; 55: 1450-1461Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 18.Dimmeler S. Haendeler J. Galle J. Zeiher A.M. Oxidized low density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases: A mechanistic clue to the "response to injury" hypothesis.Circulation. 1997; 95: 1760-1763Crossref PubMed Scopus (335) Google Scholar, 35.Harada-Shiba M. Kinoshita M. Kamido H. Shimokado K. Oxidized low density lipoprotein induces apoptosis in cultured human umbilical vein endothelial cells by common and unique mechanisms.J Biol Chem. 1998; 273: 9681-9687Crossref PubMed Scopus (233) Google Scholar and in smooth muscle cells of isolated aortas17.Galle J. Schneider R. Heinloth A. et al.Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: Role of oxidative stress.Kidney Int. 1999; 55: 1450-1461Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar. In all the cited studies, the use of antioxidants (SOD, vitamin C/E, or butylated hydroxytoluene) prevented the induction of apoptosis. Another common effect of OxLDL and AngII is the stimulation of endothelial cell proliferation19.Heinloth A. Heermeier K. Raff U. et al.Stimulation of NADPH oxidase by oxidized LDL induces proliferation of human vascular endothelial cells.J Am Soc Nephrol. 2000; 11: 1819-1825Crossref PubMed Google Scholar. The latest argument for the relevance of AngII-induced oxidative stress for endothelial dysfunction is provided by a study in patients with renovascular hypertension36.Higashi Y. Sasaki S. Nakagawa K. et al.Endothelial function and oxidative stress in renovascular hypertension.N Engl J Med. 2002; 346: 1954-1962Crossref PubMed Scopus (439) Google Scholar. In such patients with activated renin-angiotensin system and endothelial dysfunction, the response of forearm blood flow to acetylcholine, an endothelium-dependent vasodilator, was evaluated before and after renal-artery angioplasty. The forearm blood flow in response to acetylcholine was less in subjects with renovascular hypertension than in control subjects. After angioplasty, the forearm blood flow in response to acetylcholine was increased in the patients with renovascular hypertension. Interestingly, angioplasty decreased serum malondialdehyde-modified LDL, an index of oxidative stress that was positively correlated with endothelial dysfunction. The authors conclude that excessive oxidative stress is involved in endothelial dysfunction in patients with renovascular hypertension. In early stages of arteriosclerosis, enhanced oxygen radical formation already leads to endothelial dysfunction. The endothelium is a target of oxidative stress by means of attenuated endothelium-dependent dilation, enhanced cellular turnover, and cell death. However, the endothelium also contributes to the vascular state of inflammation because it is one source of O2− formation. Beside other factors, AngII and OxLDL are important stimuli for vascular oxygen radical formation, endothelial dysfunction, and cell proliferation. This work was supported by a grant from The Deutsche Forschungsgemeinschaft (DFG, SFB 355 B11).