Advertisement

Endothelin-1 and atherosclerosis: potential complications associated with endothelin-receptor blockade

  • Michael R. Dashwood
    Correspondence
    Corresponding author. Tel.: +44-20-7794-0500x5209; fax: +44-20-7830-2235
    Affiliations
    Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London NW3 2QG, UK

    Department of Surgery, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London NW3 2QG, UK
    Search for articles by this author
  • Janice C.S. Tsui
    Affiliations
    Department of Surgery, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London NW3 2QG, UK
    Search for articles by this author

      Abstract

      Atherosclerotic vascular disease remains the single most prevalent cause of death and morbidity in the western world. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that also possesses mitogenic activity on many cell types, including vascular smooth muscle cells. Raised plasma and tissue levels of ET-1 have been described in atherosclerosis in animal models and in man, suggesting that this peptide plays a pathophysiological role in this condition. Two main ET-1 receptors have been cloned (ETA and ETB). Mixed ETA/B and receptor subtype selective antagonists are now available. Since ET-1 is generally believed to be a ‘pathophysiological peptide’, we discuss the therapeutic potential of ET-1 antagonists in atherosclerosis and consider whether, at certain sites in this process, ET-1 may play a beneficial role. In such situations ET antagonism may be undesirable.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Yanagisawa 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: 411-415
        • Rubanyi G.M.
        • Polokoff M.A.
        Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology.
        Pharmacol Rev. 1994; 46: 325-415
        • Hocher B.
        • Thone-Reineke C.
        • Bauer C.
        • Raschack M.
        • Neumayer H.H.
        The paracrine endothelin system: pathophysiology and implications in clinical medicine.
        Eur J Clin Chem Clin Biochem. 1997; 35: 175-189
        • Kowala M.C.
        The role of endothelin in the pathogenesis of atherosclerosis.
        Adv Pharmacol. 1997; 37: 299-318
        • Ross R.
        Atherosclerosis – an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Ross R.
        The pathogenesis of atherosclerosis: a perspective for the 1990s.
        Nature. 1993; 362: 801-809
        • Kamat B.R.
        • Galli S.J.
        • Barger A.C.
        • Lainey L.L.
        • Silverman K.J.
        Neovascularization and coronary atherosclerotic plaque: cinematographic localization and quantitative histologic analysis.
        Hum Pathol. 1987; 18: 1036-1042
        • Barger A.C.
        • Beeuwkes R.
        • Lainey L.L.
        • Silverman K.J.
        Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis.
        N Engl J Med. 1984; 310: 175-177
        • Shi Y.
        • Pieniek M.
        • Fard A.
        • O'Brien J.
        • Mannion J.D.
        • Zalewski A.
        Adventitial remodeling after coronary arterial injury.
        Circulation. 1996; 93: 340-348
        • Barger A.C.
        • Beeuwkes R.
        Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction.
        Am J Cardiol. 1990; 66: 41G-43G
        • Zaman A.G.
        • Helft G.
        • Worthley S.G.
        • Badimon J.J.
        The role of plaque rupture and thrombosis in coronary artery disease.
        Atherosclerosis. 2000; 149: 251-266
        • Yanagisawa M.
        • Masaki T.
        Molecular biology and biochemistry of the endothelins.
        Trends Pharmacol Sci. 1989; 10: 374-378
        • Sakurai T.
        • Yanagisawa M.
        • Masaki T.
        Molecular characterization of endothelin receptors.
        Trends Pharmacol Sci. 1992; 13: 103-108
        • Schiffrin E.L.
        • Touyz R.M.
        Vascular biology of endothelin.
        J Cardiovasc Pharmacol. 1998; 32: S2-S13
        • Haller H.
        • Schaberg T.
        • Lindschau C.
        • Lode H.
        • Distler A.
        Endothelin increases [Ca2+]i, protein phosphorylation, and O2−. Production in human alveolar macrophages.
        Am J Physiol. 1991; 261: L478-L484
        • Weissberg P.L.
        • Witchell C.
        • Davenport A.P.
        • Hesketh T.R.
        • Metcalfe J.C.
        The endothelin peptides ET-1, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells.
        Atherosclerosis. 1990; 85: 257-262
        • Resink T.J.
        • Hahn A.W.
        • Scott-Burden T.
        • Powell J.
        • Weber E.
        • Buhler F.R.
        Inducible endothelin mRNA expression and peptide secretion in cultured human vascular smooth muscle cells.
        Biochem Biophys Res Commun. 1990; 168: 1303-1310
        • Alberts G.F.
        • Peifley K.A.
        • Johns A.
        • Kleha J.F.
        • Winkles J.A.
        Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop.
        J Biol Chem. 1994; 269: 10112-10118
        • Peacock A.J.
        • Dawes K.E.
        • Shock A.
        • Gray A.J.
        • Reeves J.T.
        • Laurent G.J.
        Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts.
        Am J Respir Cell Mol Biol. 1992; 7: 492-499
        • Guarda E.
        • Katwa L.C.
        • Myers P.R.
        • Tyagi S.C.
        • Weber K.T.
        Effects of endothelins on collagen turnover in cardiac fibroblasts.
        Cardiovasc Res. 1993; 27: 2130-2134
        • McMillen M.A.
        • Huribal M.
        • Cunningham M.E.
        • Kumar R.
        • Sumpio B.E.
        Endothelin-1 increases intracellular calcium in human monocytes and causes production of interleukin-6.
        Crit Care Med. 1995; 23: 34-40
        • Stankova J.
        • Rola-Pleszczynski M.
        • D'Orleans-Juste P.
        Endothelin 1 and thrombin synergistically stimulate IL-6 mRNA expression and protein production in human umbilical vein endothelial cells.
        J Cardiovasc Pharmacol. 1995; 26: S505-S507
        • Muck A.O.
        • Seeger H.
        • Korte K.
        • Lippert T.H.
        The effect of 17 β-estradiol and endothelin 1 on prostacyclin and thromboxane production in human endothelial cell cultures.
        Clin Exp Obstet Gynecol. 1993; 20: 203-206
        • Ishizuka T.
        • Takamizawa-Matsumoto M.
        • Suzuki K.
        • Kurita A.
        Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor α-stimulated vascular endothelial cells.
        Eur J Pharmacol. 1999; 369: 237-245
        • Nakano J.
        • Takizawa H.
        • Ohtoshi T.
        • Shoji S.
        • Yamaguchi M.
        • Ishii A.
        • et al.
        Endotoxin and pro-inflammatory cytokines stimulate endothelin-1 expression and release by airway epithelial cells.
        Clin Exp Allergy. 1994; 24: 330-336
        • King J.M.
        • Srivastava K.D.
        • Stefano G.B.
        • Bilfinger T.V.
        • Bahou W.F.
        • Magazine H.I.
        Human monocyte adhesion is modulated by endothelin B receptor-coupled nitric oxide release.
        J Immunol. 1997; 158: 880-886
        • Schiffrin E.L.
        • Intengan H.D.
        • Thibault G.
        • Touyz R.M.
        Clinical significance of endothelin in cardiovascular disease.
        Curr Opin Cardiol. 1997; 12: 354-367
        • Lerman A.
        • Edwards B.S.
        • Hallett J.W.
        • Heublein D.M.
        • Sandberg S.M.
        • Burnett J.C.
        Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis.
        N Engl J Med. 1991; 325: 997-1001
        • Haak T.
        • Marz W.
        • Jungmann E.
        • Hausser S.
        • Siekmeier R.
        • Gross W.
        • et al.
        Elevated endothelin levels in patients with hyperlipoproteinemia.
        Clin Investig. 1994; 72: 580-584
        • Arendt R.M.
        • Wilbert-Lampen U.
        • Heucke L.
        • Schmoeckel M.
        • Suhler K.
        • Richter W.O.
        Increased endothelin plasma concentrations in patients with coronary artery disease or hyperlipoproteinemia without coronary events.
        Res Exp Med (Berl). 1993; 193: 225-230
        • Morise T.
        • Takeuchi Y.
        • Kawano M.
        • Koni I.
        • Takeda R.
        Increased plasma levels of immunoreactive endothelin and von Willebrand factor in NIDDM patients.
        Diab Care. 1995; 18: 87-89
        • Haak T.
        • Jungmann E.
        • Felber A.
        • Hillmann U.
        • Usadel K.H.
        Increased plasma levels of endothelin in diabetic patients with hypertension.
        Am J Hypertens. 1992; 5: 161-166
        • Haak T.
        • Jungmann E.
        • Raab C.
        • Usadel K.H.
        Elevated endothelin-1 levels after cigarette smoking.
        Metabolism. 1994; 43: 267-269
        • de Nucci G.
        • Thomas R.
        • D'Orleans-Juste P.
        • Antunes E.
        • Walder C.
        • Warner T.D.
        • et al.
        Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor.
        Proc Natl Acad Sci USA. 1988; 85: 9797-9800
        • Fan J.
        • Unoki H.
        • Iwasa S.
        • Watanabe T.
        Role of endothelin-1 in atherosclerosis.
        Ann NY Acad Sci. 2000; 902: 84-93
        • Jones G.T.
        • van Rij A.M.
        • Solomon C.
        • Thomson I.A.
        • Packer S.G.
        Endothelin-1 is increased overlying atherosclerotic plaques in human arteries.
        Atherosclerosis. 1996; 124: 25-35
        • Winkles J.A.
        • Alberts G.F.
        • Brogi E.
        • Libby P.
        Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries.
        Biochem Biophys Res Commun. 1993; 191: 1081-1088
        • Timm M.
        • Kaski J.C.
        • Dashwood M.R.
        Endothelin-like immunoreactivity in atherosclerotic human coronary arteries.
        J Cardiovasc Pharmacol. 1995; 26: S442-S444
        • Dashwood M.R.
        • Sykes R.M.
        • Muddle J.R.
        • Collins M.J.
        • Prehar S.
        • Theodoropoulos S.
        • et al.
        Autoradiographic localization of [125I]endothelin binding sites in human blood vessels and coronary tissue: functional correlates.
        J Cardiovasc Pharmacol. 1991; 17: S458-S462
        • Dashwood M.R.
        • Allen S.P.
        • Luu T.N.
        • Muddle J.R.
        The effect of the ETA receptor antagonist, FR 139317, on [125I]-ET-1 binding to the atherosclerotic human coronary artery.
        Br J Pharmacol. 1994; 112: 386-389
        • Davenport A.P.
        • Kuc R.E.
        • Fitzgerald F.
        • Maguire J.J.
        • Berryman K.
        • Doherty A.M.
        [125I]-PD151242: a selective radioligand for human ETA receptors.
        Br J Pharmacol. 1994; 111: 4-6
        • Molenaar P.
        • Kuc R.E.
        • Davenport A.P.
        Characterization of two new ETB selective radioligands, [125I]-BQ3020 and [125I]-[Ala1,3,11,15]ET-1 in human heart.
        Br J Pharmacol. 1992; 107: 637-639
        • Davenport A.P.
        • O'Reilly G.
        • Kuc R.E.
        Endothelin ETA and ETB mRNA and receptors expressed by smooth muscle in the human vasculature: majority of the ETA sub-type.
        Br J Pharmacol. 1995; 114: 1110-1116
        • Kowala M.C.
        • Rose P.M.
        • Stein P.D.
        • Goller N.
        • Recce 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: 819-826
        • Iwasa S.
        • Fan J.
        • Shimokama T.
        • Nagata M.
        • Watanabe T.
        Increased immunoreactivity of endothelin-1 and endothelin B receptor in human atherosclerotic lesions. A possible role in atherogenesis.
        Atherosclerosis. 1999; 146: 93-100
        • Scotland R.
        • Vallance P.
        • Ahluwalia A.
        Endothelin alters the reactivity of vasa vasorum: mechanisms and implications for conduit vessel physiology and pathophysiology.
        Br J Pharmacol. 1999; 128: 1229-1234
        • Dashwood M.R.
        • Barker S.G.
        • Muddle J.R.
        • Yacoub M.H.
        • Martin J.F.
        [125I]-endothelin-1 binding to vasa vasorum and regions of neovascularization in human and porcine blood vessels: a possible role for endothelin in intimal hyperplasia and atherosclerosis.
        J Cardiovasc Pharmacol. 1993; 22: S343-S347
        • Dashwood M.R.
        • Jeremy J.Y.
        • Mehta D.
        • Izzat M.B.
        • Timm M.
        • Bryan A.J.
        • et al.
        Endothelin-1 and endothelin receptors in porcine saphenous vein-carotid artery grafts.
        J Cardiovasc Pharmacol. 1998; 31: S328-S330
        • Dashwood M.R.
        • Mehta D.
        • Izzat M.B.
        • Timm M.
        • Bryan A.J.
        • Angelini G.D.
        • et al.
        Distribution of endothelin-1 (ET) receptors (ET(A) and ET(B)) and immunoreactive ET-1 in porcine saphenous vein-carotid artery interposition grafts.
        Atherosclerosis. 1998; 137: 233-242
        • Katwa L.C.
        • Guarda E.
        • Weber K.T.
        Endothelin receptors in cultured adult rat cardiac fibroblasts.
        Cardiovasc Res. 1993; 27: 2125-2129
        • Xu S.
        • Denton C.P.
        • Holmes A.
        • Dashwood M.R.
        • Abraham D.J.
        • Black C.M.
        Endothelins: effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts.
        J Cardiovasc Pharmacol. 1998; 31: S360-S363
        • Schwartz S.M.
        • deBlois D.
        • O'Brien E.R.
        The intima. Soil for atherosclerosis and restenosis.
        Circ Res. 1995; 77: 445-465
        • Dashwood M.R.
        • Noertersheuser P.
        • Kirchengast M.
        • Munter K.
        Altered endothelin-1 binding following balloon angioplasty of pig coronary arteries: effect of the ETA receptor antagonist, LU 135252.
        Cardiovasc Res. 1999; 43: 445-456
        • Trachtenberg J.D.
        • Sun S.
        • Choi E.T.
        • Callow A.D.
        • Ryan U.S.
        Effect of endothelin-1 infusion on the development of intimal hyperplasia after balloon catheter injury.
        J Cardiovasc Pharmacol. 1993; 22: S355-S359
        • Douglas S.A.
        • Louden C.
        • Vickery-Clark L.M.
        • Storer B.L.
        • Hart T.
        • Feuerstein G.Z.
        • et al.
        A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.
        Circ Res. 1994; 75: 190-197
        • Martin-Nizard F.
        • Sqalli-Houssaini H.
        • Walters-Laporte E.
        • Boullier A.
        • Fruchart J.C.
        • Duriez P.
        Oxidized high-density lipoproteins modulate endothelin secretion by adult bovine aortic endothelial cells.
        J Cardiovasc Risk. 1995; 2: 263-267
        • Martin-Nizard F.
        • Houssaini H.S.
        • Lestavel-Delattre S.
        • Duriez P.
        • Fruchart J.C.
        Modified low density lipoproteins activate human macrophages to secrete immunoreactive endothelin.
        FEBS Lett. 1991; 293: 127-130
        • Boulanger C.M.
        • Tanner F.C.
        • Bea M.L.
        • Hahn A.W.
        • Werner A.
        • Luscher T.F.
        Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.
        Circ Res. 1992; 70: 1191-1197
        • Swerlick R.A.
        • Lawley T.J.
        Role of microvascular endothelial cells in inflammation.
        J Invest Dermatol. 1993; 100: 111S-115S
        • Filep J.G.
        • Sirois M.G.
        • Foldes-Filep E.
        • Rousseau A.
        • Plante G.E.
        • Fournier A.
        • et al.
        Enhancement by endothelin-1 of microvascular permeability via the activation of ETA receptors.
        Br J Pharmacol. 1993; 109: 880-886
        • Bek E.L.
        • McMillen M.A.
        Endothelins are angiogenic.
        J Cardiovasc Pharmacol. 2000; 36: S135-S139
        • Benigni A.
        • Remuzzi G.
        Endothelin antagonists.
        Lancet. 1999; 353: 133-138
        • Best P.J.
        • McKenna C.J.
        • Hasdai D.
        • Holmes Jr., D.R.
        • Lerman A.
        Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.
        Circulation. 1999; 99: 1747-1752
        • Barton M.
        • Haudenschild C.C.
        • d'Uscio L.V.
        • Shaw S.
        • Munter K.
        • Luscher T.F.
        Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice.
        Proc Natl Acad Sci USA. 1998; 95: 14367-14372
        • Wenzel R.R.
        • Fleisch M.
        • Shaw S.
        • Noll G.
        • Kaufmann U.
        • Schmitt R.
        • et al.
        Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease.
        Circulation. 1998; 98: 2235-2240
        • Goldie R.G.
        Endothelins in health and disease: an overview.
        Clin Exp Pharmacol Physiol. 1999; 26: 145-148
        • Schiffrin E.L.
        Endothelin: role in experimental hypertension.
        J Cardiovasc Pharmacol35. 2000; 35: S33-S35
        • Krum H.
        • Viskoper R.J.
        • Lacourciere Y.
        • Budde M.
        • Charlon V.
        The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan hypertension investigators.
        N Engl J Med. 1998; 338: 784-790
        • Weber C.
        • Gasser R.
        • Hopfgartner G.
        Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects.
        Drug Metab Dispos. 1999; 27: 810-815
        • Fukuroda T.
        • Fujikawa T.
        • Ozaki S.
        • Ishikawa K.
        • Yano M.
        • Nishikibe M.
        Clearance of circulating endothelin-1 by ETB receptors in rats.
        Biochem Biophys Res Commun. 1994; 199: 1461-1465
        • Clozel M.
        • Breu V.
        • Gray G.A.
        • Kalina B.
        • Loffler B.M.
        • Burri K.
        • et al.
        Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist.
        J Pharmacol Exp Ther. 1994; 270: 228-235
        • Ekelund U.
        • Adner M.
        • Edvinsson L.
        • Mellander S.
        Effects of the combined ETA and ETB receptor antagonist PD145065 on arteries, arterioles, and veins in the cat hindlimb.
        J Cardiovasc Pharmacol. 1995; 26: S211-S213
        • Davies M.J.
        • Richardson P.D.
        • Woolf N.
        • Katz D.R.
        • Mann J.
        Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content.
        Br Heart J. 1993; 69: 377-381
        • Weissberg P.L.
        • Clesham G.J.
        • Bennett M.R.
        Is vascular smooth muscle cell proliferation beneficial?.
        Lancet. 1996; 347: 305-307