Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.

Boulanger, Chantal; Tanner, Felix C.; Béa, Marie-Luce; Hahn, Alfred W.A.; Werner, Anniek; Lüscher, Thomas F.

doi:10.1161/01.res.70.6.1191

Cited by 308 publications

(132 citation statements)

References 60 publications

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“…55 Oxidized low-density lipoprotein cholesterol induces the production of ET-1 in human macrophages and increases ET release from endothelial cells. 56 Tissue ET levels have been shown to correlate with the severity of angina in patients with coronary artery disease and increase in patients with unstable angina. 57,58 ET-1 plasma levels have also been found to be elevated in patients with acute myocardial infarction and correlate with 1-year prognosis.…”

Section: Coronary Artery Diseasementioning

confidence: 99%

“…14 ET-1 biosynthesis is also stimulated by low-density lipoprotein cholesterol and glucose, and thrombin. 15,16 Endogenous inhibitors of ET-1 synthesis include nitric oxide, prostacyclin, atrial natriuretic peptides, and estrogens. [17][18][19][20] ET-1 exerts its major vascular effects through activation of 2 distinct G protein coupled ET A and ET B receptors.…”

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confidence: 99%

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Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

199

126

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Abstract-The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. Key Words: endothelin Ⅲ heart failure Ⅲ pulmonary heart disease T he endothelin (ET) system, like other vascular regulatory systems, consists of a parent peptide that undergoes enzymatic activation and exerts its biologic effects by modulating specific receptors. Of the 4 active ETs (ET 1 through 4), ET-1 is the predominant isoform in the cardiovascular system, which is generated through the cleavage of prepro ET-1 to big ET-1 and then to ET-1 by the action of ET-converting enzymes. ET-1 is found in endothelial cells and is released toward the vascular smooth muscle consistent with a paracrine role, but it is also produced by smooth muscle cells and cardiomyocytes. 1,2 ET-1 has vasoconstrictive and mitogenic effects, stimulates the production of growth factors such as vascular endothelial growth factor and basic fibroblast growth factor, and potentiates the effects of transforming growth factor-␤ and platelet-derived growth factor. 3-7 Chronic ET-1 stimulation can result in myocardial fibrosis and hypertrophy and vascular fibrosis with extracellular matrix proliferation. 8 In the lung, ET-1 is abundantly expressed in the pulmonary vasculature and appears to play an important role in the regulation of pulmonary vascular tone. 9 ET-1 is also produced in leukocytes where it influences the production of a wide range of cytokines in the inflammatory response. 10 ET is regulated in an autocrine fashion by physiochemical factors such as blood flow, pulsatile stretch, sheer stress, and pH. 11-13 Acute hypoxia leads to selective stimulation of the ET-1 gene and ET synthesis in the pulmonary vasculature. 14 ET-1 biosynthesis is also stimulated by low-density lipoprotein cholesterol and glucose, and thrombin. 15,16 Endogenous inhibitors of ET-1 synthesis include nitric oxide, prostacyclin, atrial natriuretic peptides, and estrogens. [17][18][19][20] ET-1 exerts its major vascular effects through activation of 2 distinct G protein coupled ET A and ET B receptors. ET A receptors are found in the medial smooth muscle layers of the blood vessels, and atrial and ventricular myocardium. 21 When stimulated, the ET A receptors induce vasoconstriction and cellular proliferation by increasing intracellular calcium.ET B receptors are localized on endothelial cells and, to some extent, smooth muscle cells and macrophages. 22 The activation of ET B receptors stimulates the release of nitric oxide and prostacyclin and prevents apoptosis. 23 Normally, t...

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Section: Coronary Artery Diseasementioning

confidence: 99%

mentioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

199

126

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“…70 OX-LDL also induces the expression of messenger RNA for endothelin in cultured aortic endothelial cells as well as the release of the peptide from the intact porcine aorta (Figure 8). 71 In this context it is of interest that threshold and low concentrations of endothelin, which by themselves evoke no appreciable vascular effect, potentiate contractions induced by serotonin in the human coronary artery and by norepinephrine and serotonin in the human internal mammary artery. 72 Thus, OX-LDL inhibits endotheUum-dependent relaxations and promotes endotheUum-dependent as well as endothelium-independent contractions; the consequences are alterations in vascular tone leading to vasospasm and thrombus formation, both common events in patients with coronary artery disease.…”

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confidence: 99%

Endothelial Regulation of Vascular Tone and Growth

Lüscher

Tanner

1993

American Journal of Hypertension

101

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The endothelium regulates vascular tone by releasing factors involved in relaxation and contraction, in coagulation and thrombus formation, and in growth inhibition and stimulation. Endothelium-dependent relaxations are elicited by transmitters, hormones, platelet substances, and the coagulation system, and by physical stimuli such as the shear stress from circulating blood. They are mediated by the endothelium-derived relaxing factor, recently identified as nitric oxide, which causes vasodilation and platelet deactivation. Other proposed endothelium-derived relaxing factors include a hyperpolarizing factor, lipooxygenase products, and the cytochrome P450 pathway. Endothelium-derived contracting factors are produced by the cyclooxygenase pathway and by endothelial cells, which produce the peptide endothelin-1, a potent vasoconstrictor that under normal conditions circulates at low levels. The endothelium produces both growth inhibitors-normally dominant-and growth stimuli. Denuded or dysfunctional endothelium leads to a proliferative response and intimal hyperplasia in the vessel wall; moreover, platelets adhere to the site and release potent growth factors. Endothelial dysfunction has numerous causes: Aging is associated with increased formation of contracting factor and decreased relaxing factor; denudation, such as by coronary angioplasty, impairs the capacities of regenerated endothelial cells; oxidized low-density lipoproteins and hypercholesterolemia interfere with nitric oxide production; hypertension morphologically and functionally alters the endothelium; and atherosclerosis markedly attenuates some endothelium-dependent relaxations. For patients with coronary bypass grafts, differences in endotheliumderived vasoactive factors between the internal mammary artery and the saphenous vein may be important determinants of graft function, with the mammary artery having more pronounced relaxations than the saphenous vein and thus a higher patency rate. Am J Hypertens 1993;6:283S-293S KEY WORDS: Endothelial regulation, endothelial dysfunction, vascular tone, endothelium-derived relaxing factors, endothelium-derived contracting factors, nitric oxide.T he endothelium takes part in the regulation of vascular tone 1 by releasing relaxing and contracting factors both under basal conditions and when activated by neurotransmitters, hormones, autacoids, or physical stimuli. In addition, endothelial cells release factors involved in coagulation and thrombus formation and in growth inhibition and stimulation.Owing to its strategic anatomic position, the endothelium is a target organ for hypertension, diabetes, and hyperlipidemia. 1 Alterations in endothelial function may contribute to the pathogenesis as well as to the progression and complications of hypertension and its sequelae such as atherosclerotic vascular disease. ENDOTHELIUM-DEPENDENT REGULATION OF VASCULAR TONERelaxing Factors Endothelium-dependent relaxa tions occur both in vitro and in vivo 2^; transmitters, hormones, substances derived from platelets, and t...

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“…Positive staining of endothelin-1-like immunoreactivity was observed in endothelial and medial smooth muscle cells in atherosclerotic aorta. Oxidized low-density lipoprotein, a well-established atherogenic risk factor, has been shown to induce mRNA expression and release of endothelin-1 from human and porcine macrophage and endothelial cell cultures (237,238). Furthermore, systemic administration of endothelin-1 accumulates within the atherosclerotic plaques of hypercholesterolemic rabbits (239).…”

Section: V-5 Vascular Thickeningmentioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium.

Cited by 308 publications

References 60 publications

Endothelin Receptor Blockers in Cardiovascular Disease

Endothelin Receptor Blockers in Cardiovascular Disease

Endothelial Regulation of Vascular Tone and Growth

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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