Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cellsReport as inadecuate




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Respiratory Research

, 12:137

First Online: 01 December 2011Received: 26 April 2011Accepted: 14 October 2011

Abstract

BackgroundRecent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells PASMCs and their relevance to proliferation and apoptosis in pulmonary arterial hypertension.

MethodsPrimary distal human PASMCs from patients and controls were treated with lipophilic simvastatin, atorvastatin, mevastatin and fluvastatin, lipophobic pravastatin and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release.

ResultsTreatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin NCX 6550 was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase.

ConclusionsLipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.

List of AbbreviationsET-1endothelin-1

FPPfarnesylpyrophosphate

GGPPgeranylgeranylpyrophosphate

HMG-CoA reductase3-hydroxy-3-methylglutaryl-coenzyme A reductase

IPAHidiopathic pulmonary arterial hypertension

MMP-9matrix metalloproteinase-9

MVAmevalonate

NOnitric oxide

PAHpulmonary arterial hypertension

PASMCspulmonary artery smooth muscle cells

PDGFhuman platelet-derived growth factor

PHpulmonary hypertension

PMAphorbol 12-myrisate 13-acetate

TGF-β1transforming growth factor-β1

TNF-αtumour necrosis factor-α.

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-12-137 contains supplementary material, which is available to authorized users.

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Author: Omar F Ali - Ellena J Growcott - Ghazwan S Butrous - John Wharton

Source: https://link.springer.com/







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