The Role of Endothelin in Coronary Atherosclerosis
1996; Elsevier BV; Volume: 71; Issue: 8 Linguagem: Inglês
10.1016/s0025-6196(11)64842-8
ISSN1942-5546
AutoresVerghese Mathew, David Hasdai, Amir Lerman,
Tópico(s)Renin-Angiotensin System Studies
ResumoDuring the evolution of coronary atherosclerosis, growth factors, cytokines, and other molecules are involved in cell recruitment, migration, and proliferation. Endothelin is an endothelial-derived vasoconstrictor peptide that possesses mitogenic properties. In this review, current evidence is provided that suggests that endothelin fulfills proposed criteria to be considered an atherogenic peptide because of its mitogenic and proliferative properties, as well as its interactions with known atherogenic factors. In addition, a proposed role of endothelin in the evolution of atherosclerosis is outlined. During the evolution of coronary atherosclerosis, growth factors, cytokines, and other molecules are involved in cell recruitment, migration, and proliferation. Endothelin is an endothelial-derived vasoconstrictor peptide that possesses mitogenic properties. In this review, current evidence is provided that suggests that endothelin fulfills proposed criteria to be considered an atherogenic peptide because of its mitogenic and proliferative properties, as well as its interactions with known atherogenic factors. In addition, a proposed role of endothelin in the evolution of atherosclerosis is outlined. Atherosclerosis results from an excessive inflammatory and fibroproliferative response to numerous potential vascular insults. During atherogenesis, growth factors, cytokines, lipids, and enzymes modulate critical cell functions in a manner that induces lipid accumulation and oxidation, cellmediated inflammatory response, smooth muscle proliferation, vasoconstriction, and a prothrombotic environment within the vascular wall.1Fuster V Badimon L Badimon JJ Chesebro JH The patho-genesis of coronary artery disease and the acute coronary syndromes (first of two parts).N Engl J Med. 1992; 326: 242-250Crossref PubMed Scopus (2913) Google Scholar, 2Ip JH Fuster V Badimon L Badimon J Taubman MB Chesebro JH Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.JAm Coil Cardiol. 1990; 15: 1667-1687Abstract Full Text PDF PubMed Scopus (699) Google Scholar, 3Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (9982) Google Scholar? Endothelin (ET) is an endothelial-derived peptide that exerts profound vasoconstrictive activity in vitro and in vivo. Although the role of ET as a potent systemic and coronary vasoconstrictor has been well established and reviewed extensively, an increasing body of evidence suggests that ET may have a major role in the pathogenesis and the pathophysiologic processes of coronary atherosclerosis.4Yanagisawa M Kurihara H Kimura S Tomobe Y Kobayashi M Mitsui Y et al.A novel potent vasoconstrictor peptide produced by vascular endothelial cells.Nature. 1988; 332: 411-415Crossref PubMed Scopus (10253) Google Scholar, 6Luscher TF Oemar BS Boulanger CM Hahn AWA Molecular and cellular biology of endothelin and its receptors. Part I. Part II.J Hypertens. 1993; 11 (121–126): 7-11Crossref PubMed Scopus (95) Google Scholar Whether ET is responsible for the initiation of these pathophysiologic changes is still unclear, but ET may well be a cofactor or marker of these alterations. For a peptide to have a major role in atherogenesis, it should possess certain characteristics that initiate or propagate the steps critical to the pathogenesis of atherosclerosis. (1) The peptide should participate in the pathophysiologic processes leading to atherogenesis on the cellular level. This participation includes mitogenic and proliferative properties that are mediated through specific receptors. (2) The production and activity of the peptide are enhanced by known atherogenic factors, and the circulating levels and tissue immunoreactivity are enhanced in human and animal models of atherosclerosis. (3) The peptide should also interact with these known atherogenic factors, thereby being integrated into the milieu leading to the initiation and progression of atherosclerosis. This review provides current evidence that suggests that ET fulfills the criteria to be considered an atherogenic peptide. The role of ET during the evolution of atherosclerosis and during the various clinical stages of atherosclerosis, such as endothelial dysfunction, unstable angina, acute myocardial infarction, and restenosis after percutaneous transluminal coronary angioplasty (PTCA), is outlined. Insofar as these factors may ultimately lead to left ventricular dysfunction, the role of ET in heart failure and cardiac transplantation is also briefly discussed. For a better understanding of the role of ET, the conventional knowledge of the morphologic changes and pathogenesis of atherosclerosis is examined first, and ET in the atherogenic process is discussed subsequently. Vascular endothelial injury is a critical initiating event in atherogenesis; it leads to lipid accumulation and adhesion of monocytes and platelets that, in concert with the endothelium, release various growth factors, causing migration and proliferation of smooth muscle cells. Fuster and associates1Fuster V Badimon L Badimon JJ Chesebro JH The patho-genesis of coronary artery disease and the acute coronary syndromes (first of two parts).N Engl J Med. 1992; 326: 242-250Crossref PubMed Scopus (2913) Google Scholar proposed a pathophysiologic classification of vascular injury that puts these morphologic changes into the context of the progression of atherosclerosis and the pathogenesis of acute coronary syndromes (unstable angina, myocardial infarction, and sudden cardiac death). Type I injury consists of functional alterations in the endothelium in the absence of morphologic changes, which have been described in the setting of chronic endothelial injury as a result of disturbances in blood flow, hypertension, hypercholesterolemia, and cigarette smoking.2Ip JH Fuster V Badimon L Badimon J Taubman MB Chesebro JH Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.JAm Coil Cardiol. 1990; 15: 1667-1687Abstract Full Text PDF PubMed Scopus (699) Google Scholar Although characteristic macroscopic features of atherosclerosis are not present at this stage, ample evidence suggests that this stage of endothelial dysfunction is the earliest detectable stage in the spectrum of atherosclerosis. Accumulation of lipids and monocytesmacrophages results from type I injury. In type II injury, the release of various factors by macrophages leads to the accumulation of platelets3Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (9982) Google Scholar with ensuing endothelial denudation and damage to the intima. These cells, along with the endothelium, stimulate the migration and proliferation of smooth muscle cells and may form either a fibrointimal lesion or an outer capsule on a predominantly lipid-rich lesion. A lipid lesion surrounded by a thin capsule can be disrupted to expose an extremely thrombogenic matrix and leads to type III injury, manifest by endothelial denudation with damage to the intima and media. During the evolution of atherosclerosis, growth factors, cytokines, and other molecules such as lipids are involved in cell recruitment, migration, and proliferation, as well as lipid and protein synthesis. These molecules are also intimately involved in vasomotor regulation, vascular remodeling, and coagulation. This humoral-cellular "cross-talk" has been eloquently discussed by Ross.3Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (9982) Google Scholar The role of ET and its potential importance in this series of elaborate humoral-cellular interactions are discussed in the subsequent sections. ET is a potent vasoconstrictor that was first described by Yanagisawa and colleagues in 1988.4Yanagisawa M Kurihara H Kimura S Tomobe Y Kobayashi M Mitsui Y et al.A novel potent vasoconstrictor peptide produced by vascular endothelial cells.Nature. 1988; 332: 411-415Crossref PubMed Scopus (10253) Google Scholar ET is primarily secreted by endothelial cells. A prepropeptide is cleaved to form "big" ET (39 amino acids) and then further cleaved by an ET-converting enzyme to form the 21-amino acid active peptide. The three structurally and pharmacologically distinct isopeptides-ET −1, ET−2, and ET−3-are each encoded by a different gene.5Lerman A Hildebrand Jr, FL Margulies KB O'Murchu B Perrella MA Heublein DM et al.Endothelin: a new cardiovascular regulatory peptide.Mayo Clin Proc. 1990; 65: 1441-1455Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Two distinct ET receptors exist-ET-A and ET-B. The ET-A receptor, expressed in vascular smooth muscle cells, binds ET−1, biologically active form of and is believed to mediate the profound vasoconstrictive effect associated with ET−1 through increases in intracellular calcium.6Luscher TF Oemar BS Boulanger CM Hahn AWA Molecular and cellular biology of endothelin and its receptors. Part I. Part II.J Hypertens. 1993; 11 (121–126): 7-11Crossref PubMed Scopus (95) Google Scholar A specific competitive antagonist of the ET-A receptor has been shown to cause arterial vasodilatation, a finding that demonstrates that ET exerts an effect on basal arterial vasomotor tone.7Haynes WG Webb DJ Contribution of endogenous generation of endothelin-l to basal vascular tone.Lancet. 1994; 344: 852-854Abstract PubMed Scopus (541) Google Scholar The ET-B receptor, expressed on endothelial cells and smooth muscle cells, has been reported to be associated with a dual vasodilating8Hirata Y Emori T Eguchi S Kanno K Imai T Ohta K et al.Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells.J Clin Invest. 1993; 91: 1367-1373Crossref PubMed Scopus (517) Google Scholar and vasoconstrictive9Seo B Oemar BS Siebenmann R von Segesser L Luscher TF Both ETA and ETB receptors mediate contraction to endothelin-l in human blood vessels.Circulation. 1994; 89: 1203-1208Crossref PubMed Scopus (478) Google Scholar, 10Rigel DF Lappe RW Differential responsiveness of conduit and resistance coronary arteries to endothelin A and B receptor stimulation in anesthetized dogs.J Cardiovasc Pharmacol. 1993; 22: S243-S247Crossref PubMed Scopus (36) Google Scholar response. ET is released in response to vascular injury (Fig. 1), is a strong chemoattractant for circulating monocytes, and activates macrophages.11Haller H Schaberg T Lindschau C Lode H Distler A Endothelin increases [Ca], protein phosphorylation, and 0; production in human alveolar macrophages.Am J Physiol. 1991; 261: L478-L484PubMed Google Scholar Macrophages, in tum, can then cause further injury to the overlying endothelium and also produce platelet-derived growth factor (PDGF), interleukin 1, and tumor necrosis factor-α, which can result in secondary up-regulation of PDGF production by smooth muscle cells and endothelium.3Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (9982) Google Scholar Oxidized low-density lipoprotein (LDL), one of the major participants in the atherogenic process, is a strong stimulus for ET production and secretion.12Boulanger CM Tanner FC Bea ML Hahn AW Werner A Luscher TF Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.Circ Res. 1992; 70: 1191-1197Crossref PubMed Google Scholar Smooth muscle cells are the predominant cell type in fibrous plaques, migrating to the intima and proliferating in response to cytokines released after endothelial injury.3Ross R The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809Crossref PubMed Scopus (9982) Google Scholar At least two phenotypes of smooth muscle cells have been found. In the contractile phenotype, cells respond to vasomodulating agents such as ET,5Lerman A Hildebrand Jr, FL Margulies KB O'Murchu B Perrella MA Heublein DM et al.Endothelin: a new cardiovascular regulatory peptide.Mayo Clin Proc. 1990; 65: 1441-1455Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar nitric oxide,13Moncada S, Higgs EA, editors. Nitric oxide from L-arginine: a bioregulatory system. Excerpta Medica International Congress Series No. 897,1990Google Scholar and angiotensin H,14Weber H Webb ML Serafino R Taylor DS Moreland S Norman J et al.Endothelin-I and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for common signaling mechanisms.Mol Endocrinol. 1994; 8: 148-158Crossref PubMed Scopus (86) Google Scholar whereas in the synthetic phenotype, they express several regulatory molecules,15Sjolund M Hedin D Sejersen T Heldin CH Thyberg J Arterial smooth muscle cells express platelet-derived growth factor (PDGF) A chain mRNA, secrete a PDGF-like mitogen, and bind exogenous PDGF in a phenotype- and growth state-dependent manner.J Cell Bioi. 1988; 106: 403-413Crossref PubMed Scopus (155) Google Scholar respond to growth factors by expressing appropriate receptors, and synthesize extracellular matrix. Evidence suggests that, in the development of atherosclerosis, the contractile phenotype transforms into the synthetic phenotype,15Sjolund M Hedin D Sejersen T Heldin CH Thyberg J Arterial smooth muscle cells express platelet-derived growth factor (PDGF) A chain mRNA, secrete a PDGF-like mitogen, and bind exogenous PDGF in a phenotype- and growth state-dependent manner.J Cell Bioi. 1988; 106: 403-413Crossref PubMed Scopus (155) Google Scholar a phenomenon suggesting that the vasomotor influences in early atherosclerosis are later replaced by a predominantly cellular and fibroproliferative phase. An abundance of in vitro and in vivo data have demonstrated the mitogenic effect of ET on smooth muscle cells.16Weissberg PL Witchell C Davenport AP Hesketh TR Metcalfe Je The endothelin peptides ET-l, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells.Atherosclerosis. 1990; 85: 257-262Abstract Full Text PDF PubMed Scopus (130) Google Scholar, 17Resink TJ Hahn AW Scott-Burden T Powell J Weber E Buhler FR Inducible endothelin mRNA expression and pep-tide secretion in cultured human vascular smooth muscle cells.Biochem Biophys Res Commun. 1990; 168: 1303-1310Crossref PubMed Scopus (206) Google Scholar ET has been shown to stimulate vascular smooth muscle hypertrophy and hyperplasia in cell culture systems,18Alberts GF Peifley KA Johns A Kleha JF Winkles JA Constitutive endothelin-l overexpression promotes smooth muscle cell proliferation via an external autocrine loop.J Bioi Chern. 1994; 269: 10112-10118PubMed Google Scholar and smooth muscle cells may also produce and secrete ET.17Resink TJ Hahn AW Scott-Burden T Powell J Weber E Buhler FR Inducible endothelin mRNA expression and pep-tide secretion in cultured human vascular smooth muscle cells.Biochem Biophys Res Commun. 1990; 168: 1303-1310Crossref PubMed Scopus (206) Google Scholar Moreover, constitutive ET−1 overexpression can promote smooth muscle cell proliferation,18Alberts GF Peifley KA Johns A Kleha JF Winkles JA Constitutive endothelin-l overexpression promotes smooth muscle cell proliferation via an external autocrine loop.J Bioi Chern. 1994; 269: 10112-10118PubMed Google Scholar and exogenous short-term and long-term administration of ET-1 augments neointima formation in vivo.19Douglas SA Louden C Vickery-Clark LM Storer BL Hart T Feuerstein GZ et al.A role for endogenous endothelin-l in neointimal formation after rat carotid artery balloon angio-plasty: protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.Circ Res. 1994; 75: 190-197Crossref PubMed Scopus (192) Google Scholar, 20Douglas SA Ohlstein EH Endothelin-1 promotes neointima formation after balloon angioplasty in the rat.J Cardiovasc Pharmacol. 1993; 22: S371-S373Crossref PubMed Scopus (65) Google Scholar Recent studies have suggested that ET exerts its mitogenic effect, in large part, through protein kinase C activation.21Lonchampt MO Pinelis S Goulin J Chabrier PE Braquet P Proliferation and Na+/H+ exchange activation by endothelin in vascular smooth muscle cells.Am I Hypertens. 1991; 4: 776-779PubMed Google Scholar Furthermore, in vitro studies in early-passaged, cultured aortic smooth muscle cells have shown that ET-inducedsmooth muscle cell mitogenesis and proliferation are mediated through the ET-A, but not the ET-B, receptor subtype19Douglas SA Louden C Vickery-Clark LM Storer BL Hart T Feuerstein GZ et al.A role for endogenous endothelin-l in neointimal formation after rat carotid artery balloon angio-plasty: protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.Circ Res. 1994; 75: 190-197Crossref PubMed Scopus (192) Google Scholar and that the mitogenic activity of ET correlates with ET-A receptor binding and density.22Kanse SM Wijelath E Kanthou C Newman P Kakkar VV The proliferative responsiveness of human vascular smooth muscle cells to endothelin correlates with endothelin receptor density.Lab Invest. 1995; 72: 376-382PubMed Google Scholar These results are underscored by a recent report that selective blockade of the ET-A receptor subtype decreases early atherosclerosis in hypercholesterolemic hamsters.23Kowala MC Rose PM Stein PD Goller N Reece R Beyer S et al.Selective blockade of the endothelin subtype A receptor decreases early atherosclerosis in hamsters fed cholesterol.Am J Pathol. 1995; 146: 819-826PubMed Google Scholar This mitogenic response seems to be subject to phenotypic modulation; however, investigators have also demonstrated that, in repeated passaging of smooth muscle cells into the synthetic phenotype, ET-B receptor expression is increased to the extent that selective ET-A antagonism no longer inhibits the mitogenic action of ET−1.24Serradeil-Le Gal C Herbert JM Garcia C Boutin M Maffrand IP Importance of the phenotypic state of vascular smooth muscle cells on the binding and the mitogenic activity of endothelin.Peptides. 1991; 12: 575-579Crossref PubMed Scopus (34) Google Scholar Further definition of the factors modulating this phenotypic change would be important relative to potential therapeutic implications of ET receptor antagonists. In addition, ET acts in concert with other mitogenic factors such as PDGF to induce proliferation of smooth muscle cells.16Weissberg PL Witchell C Davenport AP Hesketh TR Metcalfe Je The endothelin peptides ET-l, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells.Atherosclerosis. 1990; 85: 257-262Abstract Full Text PDF PubMed Scopus (130) Google Scholar, 25Senior RM Huang JS Griffin GL Deuel TF Dissociation of the chemotactic and mitogenic activities of platelet-derived growth factor by human neutrophil elastase.J Cell Biol. 1985; 100: 351-356Crossref PubMed Scopus (54) Google Scholar During the progression of the atherosclerotic lesion (Fig. 1), fibroblasts and the formation of extracellular matrix have a substantial role. ET has been shown in vitro to induce chemotaxis and replication of fibroblasts;26Peacock AJ Dawes KE Shock A Gray AJ Reeves JT Laurent GJ Endothelin-l and endothelin-3 induce chemo-taxis and replication of pulmonary artery fibroblasts.Am J Respir Cell Mol Bio I. 1992; 7: 492-499Crossref PubMed Scopus (133) Google Scholar this effect has been demonstrated to be mediated through the ET -A receptor subtype.27Kikuchi K Kadono T Sato S Tamaki K Takehara K Impaired growth response to endothelin-1 in scleroderma fibro-blasts.Biochem Biophys Res Commun. 1995; 207: 829-838Crossref PubMed Scopus (21) Google Scholar The proliferative effect of ET has been shown to be synergistic with the effect of insulinlike growth factor in human placental cells28Fant ME Nanu L Word RA A potential role for endothelin-1 in human placental growth: interactions with the insulin-like growth factor family of peptides.J Clin Endocrinol Metab. 1992; 74: 1158-1163Crossref PubMed Scopus (46) Google Scholar and synergistic with transforming growth factor and epidermal growth factor in mouse fibroblasts.29Yeh YC Bums ER Yeh J Yeh HW Synergistic effects of endothelin-1 (ET-1) and transforming growth factor alpha (TGF-alpha) or epidermal growth factor (EGF) on DNA replication and Gl to S phase transition.Biosci Rep. 1991; 11: 171-180Crossref PubMed Scopus (24) Google Scholar ET has also been shown to promote the production and contraction of collagen fibro blasts.30Guidry C Hook M Endothelins produced by endothelial cells promote collagen gel contraction by fibroblasts.J Cell BioI. 1991; 115: 873-880Crossref PubMed Scopus (67) Google Scholar ET has been shown to promote microvascular platelet thrombus formation31Halim A Kanayama N el Maradny E Maehara K Terao T Coagulation in vivo microcirculation and in vitro caused by endothelin-1.Thromb Res. 1993; 72: 203-209Abstract Full Text PDF PubMed Scopus (39) Google Scholar and therefore may contribute to acute coronary syndromes in this manner. Of interest, however, the ET-B receptor subtype has been demonstrated to have an antiaggregatory effect on platelets,32Leadley Jr, RJ Lee P Erickson LA Shebuski RJ The snake venom peptide sarafotoxin S6b inhibits repetitive platelet thrombus formation in the stenosed canine coronary artery.J Cardiovasc Pharmacol. 1993; 22: S199-S203Crossref PubMed Scopus (4) Google Scholar, 33McMurdo L Lidbury PS Thiemermann C Vane JR Mediation of endothelin-l-induced inhibition of platelet aggregation via the ETB receptor.Br J Pharmacol. 1993; 109: 530-534Crossref PubMed Scopus (24) Google Scholar suggesting that the prothrombotic effects of ET on platelets are ET-A mediated. This evidence implies that ET has an important role in the initiation and progression of cellular pathways leading to atherogenesis. In addition, the potent coronary vasoconstrictive properties of ET34Cannan CR Burnett Jr, JC Brandt RR Lerman A Endothelin at pathophysiological concentrations mediates coronary vasoconstriction via the endothelin-A receptor.Circulation. 1995; 92: 3312-3317Crossref PubMed Scopus (54) Google Scholar may potentiate the atherosclerotic process by reducing blood flow and subsequently enhancing platelet aggregation and thrombus formation. Several atherogenic risk factors have been found to be associated with ET activity. Conventional modifiable risk factors for atherosclerotic vascular disease include hyperlipidemia, smoking, hypertension, and diabetes. Investigators have demonstrated that ET production and secretion are enhanced in the presence of oxidized LDL, specifically in cultured endothelial cells, intact blood vessels, and macrophages.12Boulanger CM Tanner FC Bea ML Hahn AW Werner A Luscher TF Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.Circ Res. 1992; 70: 1191-1197Crossref PubMed Google Scholar, 35Martin-Nizard F Houssaini HS Lestavel-Delattre S Duriez P Fruchart Je Modified low density lipoproteins activate human macrophages to secrete immunoreactive endothelin.FEBS Lett. 1991; 293: 127-130Crossref PubMed Scopus (71) Google Scholar Oxidized LDL has also been shown to increase superoxide production by human alveolar macrophages.11Haller H Schaberg T Lindschau C Lode H Distler A Endothelin increases [Ca], protein phosphorylation, and 0; production in human alveolar macrophages.Am J Physiol. 1991; 261: L478-L484PubMed Google Scholar Uptake of oxidized LDL by the macrophages results in formation of foam cells and may alter expression of various regulatory hormones. Enhanced plasma levels and tissue ET immunoreactivity have been demonstrated in the early stage of coronary atherosclerosis in experimental models and in humans. ET-l has been shown to be increased in hypercholesterolemic rats before the onset of morphologic changes in the vasculature.36Horio T Kohno M Murakawa K Yasunari K Yokokawa K Ueda M et al.Increased plasma immunoreactive endothelin-1 concentration in hypercholesterolemic rats.Atherosclerosis. 1991; 89: 239-246Abstract Full Text PDF PubMed Scopus (43) Google Scholar A high cholesterol diet in pigs resulted in coronary endothelial dysfunction, an increase in circulating ET concentrations, and enhanced coronary artery ET tissue immunoreactivity (Fig. 2); moreover, the administration of intracoronary acetylcholine resulted in a further increase in plasma ET concentrations that correlated with the degree of coronary vasoconstriction.37Lerman A Webster MW Chesebro JH Edwards WD Wei CM Fuster V et al.Circulating and tissue endothelin immu-noreactivity in hypercholesterolemic pigs.Circulation. 1993; 88: 2923-2928Crossref PubMed Scopus (151) Google Scholar Patients with increased total serum cholesterol and Lp(a) lipoprotein levels have been shown to have elevated circulating levels of ET.38Haak T Marz W Jungmann E Hausser S Siekmeier R Gross W et al.Elevated endothelin levels in patients with hyperlipoproteinemia.Clin Invest. 1994; 72: 580-584PubMed Google Scholar Circulating levels and tissue ET immunoreactivity are enhanced in advanced atherosclerosis in humans and correlate with the severity of disease.39Lerman A Edwards BS Hallett JW Heublein DM Sandberg SM Burnett Jr, JC Circulating and tissue endothelin immu-noreactivity in advanced atherosclerosis.N Engl J Med. 1991; 325: 997-1001Crossref PubMed Scopus (943) Google Scholar ET has been shown to be increased in association with cigarette smoking,40Haak T Jungmann E Raab C Usadel KH Elevated endothelin-1 levels after cigarette smoking.Metabolism. 1994; 43: 267-269Abstract Full Text PDF PubMed Scopus (152) Google Scholar and enhanced vasoconstriction in response to low-dose exogenously administered ET has been demonstrated in smokers.41Kiowski W Linder L Stoschitzky K Pfisterer M Burckhardt D Burkart F et al.Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhanced vaso-constriction to exogenously administered endothelin-l in clinically healthy smokers.Circulation. 1994; 90: 27-34Crossref PubMed Scopus (240) Google Scholar In contrast, the role of ET in essential hypertension is still controversial and may be related to the degree of vascular disease associated with hypertension.42Schiffrin EL Endothelin in hypertension.Curr Opin Cardiol. 1995; 10: 485-494Crossref PubMed Scopus (22) Google Scholar ET may have a pivotal role in the clinical stages of coronary atherosclerosis, from the early stage of coronary endothelial dysfunction that progresses to myocardial ischemia, acute myocardial infarction, heart failure, and cardiac transplantation (Fig. 3). ET may have a role as a marker or as a participant in early coronary atherosclerosis. The endothelium functions as the principal modulator of vascular tone by producing and releasing vasoactive substances such as endothelium-derived relaxing factor (EDRF) with its vasodilating and antiproliferative properties, as well as ET with its vasoconstrictive and mitogenic properties. Thus, maintenance of coronary vasomotor tone implies a balance between these factors. Imbalances between these factors have been implicated in cardiovascular disease states such as hypercholesterolemia, atherosclerosis, hypertension, and congestive heart failure.43Lerman A Burnett Jr, JC Intact and altered endothelium in regulation of vasomotion.Circulation. 1992; 86: IIII2-IIII9Google Scholar Such imbalance may stem from a relative lack of EDRF activity, excess of ET, or both. Regardless, the observed net effect has been a relative increase in coronary vasomotor tone and a relative decrease in coronary blood flow. Endothelial injury is the stimulus that triggers atherogenesis based on the response to injury hypothesis.' A precise definition of endothelial injury is difficult because changes in integrity of the endothelial lining may not be manifest morphologically. Endothelial dysfunction has been demonstrated in disease states such as hypercholesterol emia,44Flavahan NA Atherosclerosis or lipoprotein-induced endo-thelial dysfunction: potential mechanisms underlying reduction in EDRF/nitric oxide activity.Circulation. 1992; 85: 1927-1938Crossref PubMed Scopus (445) Google Scholar, 45Zeiher AM Drexler H Saurbier B Just H Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension.I Clin Invest. 1993; 92: 652-662Crossref PubMed Scopus (629) Google Scholar atherosclerosis, heart failure, and hypertension,45Zeiher AM Drexler H Saurbier B Just H Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension.I Clin Invest. 1993; 92: 652-662Crossref PubMed Scopus (629) Google Scholar which are also characterized by increased plasma ET concentrations. The assessment of endothelial function in the human coronary vascular bed with use of acetylcholine has been previously described.45Zeiher AM Drexler H Saurbier B Just H Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension.I Clin Invest. 1993; 92: 652-662Crossref PubMed Scopus (629) Google Scholar, 46Cannan CR McGoon M Holmes Jr, DR Lerman A Altered coronary endothelial function in a patient with asymptomatic left ventricular dysfunction.Int J Cardiol. 1996; 53: 147-151Abstract Full Text PDF PubMed Scopus (14) Google Scholar Patients with endothelial dysfunction who do not have significant angiographically detectable atherosclerosis are characterized by a decrease in coronary blood flow in response to the endothelial-dependent vasodilator acetylcholine.45Zeiher AM Drexler H Saurbier B Just H Endothelium-mediated coronary blood flow modulat
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