Home LiteratureArticle Details
PMID: 9826706 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 24 ·1998-11-24 ·Pages 14367-72

Barton M, Haudenschild CC, d'Uscio LV, Shaw S, Münter K, Lüscher TF

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.

MeSH Terms
Acetylcholine/pharmacology Animals Aorta, Thoracic/drug effects,pathology,physiopathology Apolipoproteins E/deficiency Arteriosclerosis/pathology,physiopathology,prevention & control Blood Pressure/drug effects Cholesterol/blood Diet Endothelin Receptor Antagonists Endothelin-1/blood,pharmacology,physiology Endothelium, Vascular/drug effects,physiology,physiopathology Humans In Vitro Techniques Lipoproteins/blood Male Mice Mice, Inbred C57BL Mice, Mutant Strains Muscle, Smooth, Vascular/drug effects,pathology,physiopathology Nitric Oxide/physiology Nitroprusside/pharmacology Norepinephrine/pharmacology Phenylpropionates/pharmacology Pyrimidines/pharmacology Receptor, Endothelin A Species Specificity Systole Triglycerides/blood Vasodilation/drug effects
Chemicals
Apolipoproteins E Endothelin Receptor Antagonists Endothelin-1 Lipoproteins Phenylpropionates Pyrimidines Receptor, Endothelin A Triglycerides Nitroprusside Nitric Oxide darusentan Cholesterol Acetylcholine Norepinephrine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Barton M
Cardiology, University Hospital Zürich and Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, CH-8091 Zurich, Switzerland.
Haudenschild C C
d'Uscio L V
Shaw S
Münter K
Lüscher T F
References (57)
57 references, click to expand
  1. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines.
    Circulation. 1992 Apr;85(4):1390-7 PMID: 1555281
  2. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels.
    Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2479-88 PMID: 9409218
  3. Some statistical methods useful in circulation research.
    Circ Res. 1980 Jul;47(1):1-9 PMID: 7379260
  4. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.
    N Engl J Med. 1986 Oct 23;315(17):1046-51 PMID: 3093861
  5. Increased vasodilator responses to acetylcholine in psychosocial hypertensive mice.
    Hypertension. 1987 Mar;9(3):268-76 PMID: 3028955
  6. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
    Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265-9 PMID: 2827174
  7. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries.
    Circ Res. 1988 Feb;62(2):185-90 PMID: 2448055
  8. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.
    Nature. 1988 Mar 31;332(6163):411-5 PMID: 2451132
  9. Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit.
    Hypertension. 1989 Aug;14(2):203-9 PMID: 2759679
  10. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide.
    J Clin Invest. 1990 Feb;85(2):587-90 PMID: 2153712
  11. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm?
    Circulation. 1990 Jul;82(1):188-95 PMID: 2194695
  12. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages.
    J Exp Med. 1990 Dec 1;172(6):1741-8 PMID: 1701822
  13. Cloning and expression of a cDNA encoding an endothelin receptor.
    Nature. 1990 Dec 20-27;348(6303):730-2 PMID: 2175396
  14. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.
    Nature. 1990 Dec 20-27;348(6303):732-5 PMID: 2175397
  15. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function.
    Cell Regul. 1990 Aug;1(9):649-59 PMID: 2078571
  16. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis.
    N Engl J Med. 1991 Oct 3;325(14):997-1001 PMID: 1886637
  17. Endothelins produced by endothelial cells promote collagen gel contraction by fibroblasts.
    J Cell Biol. 1991 Nov;115(3):873-80 PMID: 1918166
  18. Endothelin increases [Ca2+]i, protein phosphorylation, and O2-. production in human alveolar macrophages.
    Am J Physiol. 1991 Dec;261(6 Pt 1):L478-84 PMID: 1662920
  19. Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.
    Circ Res. 1992 Jun;70(6):1191-7 PMID: 1315634
  20. Molecular cloning and characterization of human endothelial nitric oxide synthase.
    FEBS Lett. 1992 Aug 3;307(3):287-93 PMID: 1379542
  21. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.
    Science. 1992 Oct 16;258(5081):468-71 PMID: 1411543
  22. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.
    Cell. 1992 Oct 16;71(2):343-53 PMID: 1423598
  23. Cloning and expression of a cDNA encoding human endothelium-derived relating factor/nitric oxide synthase.
    J Biol Chem. 1992 Nov 5;267(31):22694 PMID: 1385404
  24. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase.
    J Clin Invest. 1992 Nov;90(5):2092-6 PMID: 1385480
  25. Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries.
    Biochem Biophys Res Commun. 1993 Mar 31;191(3):1081-8 PMID: 8466485
  26. Endothelial dysfunction in coronary artery disease.
    Annu Rev Med. 1993;44:395-418 PMID: 8476260
  27. The pathogenesis of atherosclerosis: a perspective for the 1990s.
    Nature. 1993 Apr 29;362(6423):801-9 PMID: 8479518
  28. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension.
    J Clin Invest. 1993 Aug;92(2):652-62 PMID: 8349804
  29. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression.
    Arterioscler Thromb. 1994 Jan;14(1):141-7 PMID: 8274470
  30. Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit.
    J Am Coll Cardiol. 1994 Feb;23(2):452-8 PMID: 8294700
  31. Superoxide and peroxynitrite in atherosclerosis.
    Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1044-8 PMID: 8302829
  32. Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop.
    J Biol Chem. 1994 Apr 1;269(13):10112-8 PMID: 8144511
  33. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum.
    Arterioscler Thromb. 1994 Apr;14(4):605-16 PMID: 7511933
  34. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation.
    Arterioscler Thromb. 1994 May;14(5):746-52 PMID: 8172852
  35. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits.
    Arterioscler Thromb. 1994 May;14(5):753-9 PMID: 7513551
  36. Increased tissue endothelin immunoreactivity in atherosclerotic lesions associated with acute coronary syndromes.
    Lancet. 1994 Nov 19;344(8934):1405-6 PMID: 7968078
  37. Angiotensin II and endothelin-1 increase fibroblast growth factor-2 mRNA expression in vascular smooth muscle cells.
    Biochem Biophys Res Commun. 1998 Jan 6;242(1):202-8 PMID: 9439636
  38. Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone.
    J Physiol Pharmacol. 1997 Dec;48(4):675-88 PMID: 9444616
  39. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension.
    Hypertension. 1998 Jan;31(1 Pt 2):499-504 PMID: 9453352
  40. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.
    J Clin Invest. 1998 Feb 15;101(4):731-6 PMID: 9466966
  41. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis.
    Circulation. 1998 Jun 30;97(25):2494-8 PMID: 9657467
  42. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. A clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina.
    Circulation. 1995 Feb 15;91(4):941-7 PMID: 7850978
  43. The proliferative responsiveness of human vascular smooth muscle cells to endothelin correlates with endothelin receptor density.
    Lab Invest. 1995 Mar;72(3):376-82 PMID: 7898056
  44. Modulation of particulate nitric oxide synthase activity and peroxynitrite synthesis in cholesterol enriched endothelial cell membranes.
    Biochem Pharmacol. 1995 May 26;49(11):1589-600 PMID: 7540391
  45. Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression.
    J Clin Invest. 1995 Aug;96(2):1059-65 PMID: 7635942
  46. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model.
    Am J Pathol. 1995 Aug;147(2):267-77 PMID: 7639326
  47. Hypertension in mice lacking the gene for endothelial nitric oxide synthase.
    Nature. 1995 Sep 21;377(6546):239-42 PMID: 7545787
  48. Regional variations in ETA/ETB binding sites in human coronary vasculature.
    J Cardiovasc Pharmacol. 1995;26 Suppl 3:S351-4 PMID: 8587412
  49. Mouse models of atherosclerosis.
    Science. 1996 May 3;272(5262):685-8 PMID: 8614828
  50. Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists.
    J Med Chem. 1996 May 24;39(11):2123-8 PMID: 8667356
  51. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.
    Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37 PMID: 8944624
  52. L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.
    Circulation. 1997 Jan 21;95(2):430-7 PMID: 9008461
  53. Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells.
    Hypertension. 1997 Jan;29(1 Pt 1):65-9 PMID: 9039082
  54. Basal nitric oxide synthesis in essential hypertension.
    Lancet. 1997 Mar 22;349(9055):837-42 PMID: 9121259
  55. 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 Sep 29;238(3):861-5 PMID: 9325182
  56. Atherosclerosis, vascular remodeling, and impairment of endothelium-dependent relaxation in genetically altered hyperlipidemic mice.
    Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2333-40 PMID: 9409199
  57. Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity.
    Circulation. 1992 May;85(5):1927-38 PMID: 1572048
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.24.14367
Published
1998-11-24
Pages
14367-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC24379
Subset
IM
Grants
NHLBI NIH HHS · R01-HL-54246 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.24.14367 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2