TY - JOUR
T1 - HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome
AU - Hermida, Nerea
AU - Markl, Andreas
AU - Hamelet, Julien
AU - Van Assche, Tim
AU - Vanderper, Annelies
AU - Herijgers, Paul
AU - van Bilsen, Marc
AU - Hilfiker-Kleiner, Denise
AU - Noppe, Gauthier
AU - Beauloye, Christophe
AU - Horman, Sandrine
AU - Balligand, Jean-Luc
PY - 2013/7/1
Y1 - 2013/7/1
N2 - 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. 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). In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.
AB - 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. 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). In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.
KW - Myocardial fibrosis
KW - Diastolic dysfunction
KW - Metabolic syndrome
KW - AMPK
U2 - 10.1093/cvr/cvt070
DO - 10.1093/cvr/cvt070
M3 - Article
C2 - 23542580
SN - 0008-6363
VL - 99
SP - 44
EP - 54
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -