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HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome.

Abstract：

AIMS:The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties. METHODS AND RESULTS:We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output). CONCLUSION:In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Hermida N,Markl A,Hamelet J,Van Assche T,Vanderper A,Herijgers P,van Bilsen M,Hilfiker-Kleiner D,Noppe G,Beauloye C,Horman S,Balligand JL

doi

10.1093/cvr/cvt070

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

44-54

issue

eissn

0008-6363

issn

1755-3245

pii

cvt070

journal_volume

pub_type

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HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome.