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

作者：Hermida Nerea; Markl Andreas; Hamelet Julien; Van Assche Tim; Vanderper Annelies; Herijgers Paul; van Bilsen Marc; Hilfiker Kleiner Denise; Noppe Gauthier; Beauloye Christophe; Horman Sandrine; Balligand Jean Luc^*

来源：Cardiovascular Research, 2013, 99(1): 44-54.

DOI：10.1093/cvr/cvt070

• Myocardial fibrosis
• Diastolic dysfunction
• Metabolic syndrome
• AMPK

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. %26lt;br%26gt;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-(1) and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-(1) 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 AMPK1/2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by PV loop analysis (slope of EDPVR, dP/dt min and cardiac output). %26lt;br%26gt;In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.

• 出版日期2013-7-1