Endothelin ETA Receptor Blockade Restores NO-mediated Endothelial Function and Inhibits Atherosclerosis in Apolipoprotein E-deficient Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1998 Nov 25

PMID 9826706

Citations 73

Authors

M Barton

C C Haudenschild

L V dUscio

S Shaw

K Munter

T F Luscher

Affiliations

Soon will be listed here.

Abstract

This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ETA receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 +/- 3 vs. 99 +/- 2%, P < 0.0001) and plasma nitrate were reduced (57.9 +/- 4 vs. 93 +/- 10 micromol/liter, P < 0.01). Treatment with the ETA receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 +/- 3 to 93 +/- 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 +/- 4 to 80 +/- 8.3 micromol/liter, P < 0.05). Chronic ETA receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ETA receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ETA receptor blockade may have therapeutic potential in patients with atherosclerosis.

Citing Articles

Influence of Atherosclerosis-Associated Risk Factors on Expression of Endothelin Receptors in Advanced Atherosclerosis.

Herbers O, Holtke C, Usai M, Hochhalter J, Mallik M, Wildgruber M Int J Mol Sci. 2025; 26(5).

PMID: 40076930 PMC: 11899768. DOI: 10.3390/ijms26052310.

The metabolism of big endothelin-1 axis and lipids affects carotid atherosclerotic plaque stability - the possible opposite effects of treatment with statins and aspirin.

Plonski A, Krupa A, Pawlak D, Sokolowska K, Sieklucka B, Gabriel M Pharmacol Rep. 2025; .

PMID: 40063220 DOI: 10.1007/s43440-025-00714-9.

The Role of Polymorphism in the Endothelial Homeostasis and Vitamin D Metabolism Genes in the Severity of Coronary Artery Disease.

Ponasenko A, Sinitskaya A, Sinitsky M, Khutornaya M, Barbarash O Biomedicines. 2023; 11(9).

PMID: 37760823 PMC: 10526004. DOI: 10.3390/biomedicines11092382.

Epigenetically altered macrophages promote development of diabetes-associated atherosclerosis.

Huang D, Gao W, Zhong X, Wu H, Zhou Y, Ma Y Front Immunol. 2023; 14:1196704.

PMID: 37215106 PMC: 10196132. DOI: 10.3389/fimmu.2023.1196704.

Endothelin Receptor Antagonists in Kidney Disease.

Martinez-Diaz I, Martos N, Llorens-Cebria C, Alvarez F, Bedard P, Vergara A Int J Mol Sci. 2023; 24(4).

PMID: 36834836 PMC: 9965540. DOI: 10.3390/ijms24043427.

References

Dashwood M, Timm M, Kaski J . Regional variations in ETA/ETB binding sites in human coronary vasculature. J Cardiovasc Pharmacol. 1995; 26 Suppl 3:S351-4. View

Nishida K, Harrison D, Navas J, Fisher A, Dockery S, Uematsu M . Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest. 1992; 90(5):2092-6. PMC: 443276. DOI: 10.1172/JCI116092. View

Lerman A, Edwards B, HALLETT J, Heublein D, Sandberg S, Burnett Jr J . Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991; 325(14):997-1001. DOI: 10.1056/NEJM199110033251404. View

Zeiher A, Drexler H, Saurbier B, Just H . Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993; 92(2):652-62. PMC: 294898. DOI: 10.1172/JCI116634. View

Wang B, Singer A, Tsao P, Drexler H, Kosek J, Cooke J . Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit. J Am Coll Cardiol. 1994; 23(2):452-8. DOI: 10.1016/0735-1097(94)90433-2. View

Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S . Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990; 348(6303):730-2. DOI: 10.1038/348730a0. View

Barton M, Shaw S, dUscio L, Moreau P, Luscher T . 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(3):861-5. DOI: 10.1006/bbrc.1997.7394. View

Zhang S, Reddick R, Piedrahita J, Maeda N . Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258(5081):468-71. DOI: 10.1126/science.1411543. View

Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K . Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990; 348(6303):732-5. DOI: 10.1038/348732a0. View

10.

Hahn A, Resink T, Powell J, Dohi Y, Buhler F . Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul. 1990; 1(9):649-59. PMC: 361629. DOI: 10.1091/mbc.1.9.649. View

11.

Alberts G, Peifley K, Johns A, Kleha J, Winkles J . Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. J Biol Chem. 1994; 269(13):10112-8. View

12.

Wallenstein S, Zucker C, Fleiss J . Some statistical methods useful in circulation research. Circ Res. 1980; 47(1):1-9. DOI: 10.1161/01.res.47.1.1. View

13.

Flavahan N . Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation. 1992; 85(5):1927-38. DOI: 10.1161/01.cir.85.5.1927. View

14.

Ehrenreich H, Anderson R, Fox C, Rieckmann P, Hoffman G, Travis W . Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med. 1990; 172(6):1741-8. PMC: 2188743. DOI: 10.1084/jem.172.6.1741. View

15.

Kanse S, Wijelath E, Kanthou C, Newman P, Kakkar V . The proliferative responsiveness of human vascular smooth muscle cells to endothelin correlates with endothelin receptor density. Lab Invest. 1995; 72(3):376-82. View

16.

Guidry C, Hook M . Endothelins produced by endothelial cells promote collagen gel contraction by fibroblasts. J Cell Biol. 1991; 115(3):873-80. PMC: 2289172. DOI: 10.1083/jcb.115.3.873. View

17.

Webb R, Vander A, Henry J . Increased vasodilator responses to acetylcholine in psychosocial hypertensive mice. Hypertension. 1987; 9(3):268-76. DOI: 10.1161/01.hyp.9.3.268. View

18.

Yang Z, Richard V, von Segesser L, Bauer E, Stulz P, Turina M . Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm?. Circulation. 1990; 82(1):188-95. DOI: 10.1161/01.cir.82.1.188. View

19.

Ruetten H, Thiemermann C . Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone. J Physiol Pharmacol. 1998; 48(4):675-88. View

20.

Barton M, dUscio L, Shaw S, Meyer P, Moreau P, Luscher T . ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998; 31(1 Pt 2):499-504. DOI: 10.1161/01.hyp.31.1.499. View