Endothelin-1 in Humans is Increased by Oxygen-Derived Radicals Ex Vivo and in Vivo

Abstract

Endothelin-1, angiotensin II, and oxygen-derived radicals are pivotal factors in the development and progression of atherosclerosis. In vitro studies suggest that generation of oxygen-derived radicals by angiotensin II is an important mechanism increasing endothelin-1 synthesis, which consecutively may trigger effects such as cell proliferation and hypertrophy. The aim of this study was to confirm our previous data in an ex vivo and an in vivo setting.

Explanted segments of internal mammary arteries were analyzed for big endothelin-1 expression following incubation with xanthine oxidase, angiotensin II, superoxide dismutase, and catalase to stimulate or to specifically inactivate oxygen-derived radicals. Endothelin-1 concentrations were determined by immunostaining and enzyme-linked immunosorbent assay. Further, oxypurinol was given to patients undergoing coronary angioplasty, a procedure known to increase plasma endothelin-1 concentrations.

Angiotensin II and xanthine oxidase dose-dependently increased big endothelin-1 concentrations (p < .01 and p < .0001); the effects could be inhibited by coincubation with superoxide dismutase and catalase as determined by both semiquantitative immunofluorescence and enzyme-linked immunosorbent assay (p < .01). Patients undergoing coronary angioplasty exhibited significantly elevated big endothelin-1 concentrations 60 minutes after angioplasty (p = .03); in patients also receiving oxypurinol immediately after angioplasty, big endothelin-1 concentrations decreased (p = .001).

Our results may explain the association between elevated angiotensin II levels, increased oxidative stress, and increased endothelin-1 concentrations in atherosclerosis. The data therefore support the concept that oxygen-derived free radicals stimulate the release of endothelin-1, which subsequently induces effects such as proliferation and enhanced agonist-induced vasoconstriction, previously attributed directly to angiotensin II.

Keywords

endothelin-1 angiotensin II oxygen-derived radicals oxypurinol

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References

Yanagisawa

, Kurihara

, Kimura

, . A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–5.

Rajagopalan

, Kurz

, Munzel

, . 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;97:1916–23.

Lerman

, Edwards

, Hallett

, . Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991;325:997–1001.

Zeiher

AM.

Endothelial vasodilator dysfunction: pathogenetic link to myocardial ischaemia or epiphenomenon?

Lancet 1996;348 Suppl 1:s10–2.

Morgan

, Baker

KM.

Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation 1991;83:13–25.

Griendling

, Minieri

, Ollerenshaw

, Alexander

RW.

Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141–8.

Alexander

, Cockrell

, Rinewalt

, . Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension. Am J Physiol Regul Integr Comp Physiol 2001;280:R1388–92.

Ballew

, Fink

GD.

Role of ET(A) receptors in experimental ANG II-induced hypertension in rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R150–4.

Barton

, Shaw

, d'Uscio

, . Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. Biochem Biophys Res Commun 1997;238:861–5.

10.

Barton

, Shaw

, d'Uscio

, . Differential modulation of the renal and myocardial endothelin system by angiotensin II in vivo. Effects of chronic selective ETA receptor blockade. J Cardiovasc Pharmacol 1998;31 Suppl 1:S265–8.

11.

Kaehler

, Mendel

, Weckmueller

, . Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter. J Mol Cell Cardiol 2000;32:1429–37.

12.

Busse

, Fleming

, Hecker

Signal transduction in endothelium-dependent vasodilatation. Eur Heart J 1993;14 Suppl I:2–9.

13.

Guyton

, Gorospe

, Wang

, . Age-related changes in activation of mitogen-activated protein kinase cascades by oxidative stress. J Investig Dermatol Symp Proc 1998;3:23–7.

14.

Love

, Keenan

AK.

Cytotoxicity-associated effects of reactive oxygen species on endothelin-1 secretion by pulmonary endothelial cells. Free Radic Biol Med 1998;24:1437–45.

15.

Hughes

, Stricklett

, Padilla

, Kohan

DE.

Effect of reactive oxygen species on endothelin-1 production by human mesangial cells. Kidney Int 1996;49:181–9.

16.

Michael

, Markewitz

, Kohan

DE.

Oxidant stress regulates basal endothelin-1 production by cultured rat pulmonary endothelial cells. Am J Physiol 1997;273L768–74.

17.

Spiekermann

, Landmesser

, Dikalov

, . 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;107:1383–9.

18.

Cardillo

, Kilcoyne

, Cannon

III , . Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 1997;30:57–63.

19.

Carpenter

, Stenmark

KR.

Endothelin receptor blockade decreases lung water in young rats exposed to viral infection and hypoxia. Am J Physiol Lung Cell Mol Physiol 2000;279L547–54.

20.

Baldus

, Koester

, Chumley

, . Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease. Free Radic Biol Med 2005;39:1184–90.

21.

Kaehler

, Sill

, Koester

, . Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species. Clin Sci (Lond) 2002;103 Suppl 48:176S–8S.

22.

Kaehler

, Ewert

, Weckmueller

, . Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells. J Cardiovasc Pharmacol 2001;38:49–57.

23.

Miller

Jr , Gutterman

, Rios

, . Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 1998;82:1298–305.

24.

Hojo

, Ikeda

, Katsuki

, . Release of endothelin 1 and angiotensin II induced by percutaneous transluminal coronary angioplasty. Catheter Cardiovasc Interv 2000;51:42–9.

25.

Davlouros

, Simeonidou

, Tsakas

, . Release of endothelin-1 from human endocardium after radiofrequency catheter ablation and coronary angioplasty: comparative results. Int J Cardiol 2005;102:187–93.

26.

Taylor

, Bobik

, Richards

, . Myocardial endothelin-1 release and indices of inflammation during angioplasty for acute myocardial infarction and stable coronary artery disease. Am Heart J 2004;148:e10.

27.

Meneshian

, Bulkley

GB.

The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction. Microcirculation 2002;9:161–75.

28.

White

, Darley-Usmar

, Berrington

, . Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci U S A 1996;93:8745–9.

29.

Sobey

, Dalipram

, Dusting

, Woodman

OL.

Impaired endothelium-dependent relaxation of dog coronary arteries after myocardial ischaemia and reperfusion: prevention by amlodipine, propranolol and allopurinol. Br J Pharmacol 1992;105:557–62.

30.

Guthikonda

, Sinkey

, Barenz

, Haynes

WG.

Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation 2003;107:416–21.

31.

Geng

, Rong

, Lau

BH.

S-allyl cysteine inhibits activation of nuclear factor kappa B in human T cells. Free Radic Biol Med 1997;23:345–50.

32.

Bierhaus

, Chevion

, . Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 1997;46:1481–90.

33.

Gryglewski

, Palmer

, Moncada

Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 1986;320:454–6.