Abstract 18122: HMGCoA Reductase Inhibition Reverses Myocardial Fibrosis and Diastolic Dysfunction Through AMPK Activation in a Mouse Model of Metabolic Syndrome
In mice deficient in both leptin and the LDL-receptor (LDLr x ob/ob -/- mice, DKO) presenting all features of the metabolic syndrome, we previously showed that statins improved insulin sensitivity and reduced blood pressure variability in the absence of body weight loss or change in plasma cholesterol. When compared with leptin-only deficient mice, DKO also exhibit impaired diastolic relaxation and loss of contractile reserve. We now studied the effects of chronic statin treatment on cardiac remodeling, e.g. diastolic properties of DKO mice. We treated DKO mice (12 weeks) with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass (left ventricular mass index: 123.34 ± 11.86 vs 158.46 ± 14.15, P<0.05; left ventricular posterior wall thickness in diastole: 0,79 ± 0.13 vs 1.03 ± 0.12, P<0.05) and increased left ventricular end diastolic volume (52.70 ± 6.75 vs 38,88 ± 7,43, P<0.05), but in absence of significant effect (by histomorphometry) on cardiomyocyte dimensions by WGA staining. Similarly, R had no effect on the hypertrophic response to PE, ET-1 or Iso (ANP, BNP expression) in isolated cardiomyocytes in vitro. Conversely, R reversed the age-dependent development of myocardial fibrosis assessed by Picrosirius Red staining (7.02 ± 0,81 vs 12.72 ± 0.56, P<0.01) as well as RNA expression for several pro-fibrotic markers (Procollagen type I, procollagen type I carboxy-terminal proteinase or PCP, its enhancer or PCPE, and lysyl oxidase or LOX). Moreover, R presented also antifibrotic effects in neonatal cardiac fibroblasts (NCF) assessed by the expression of procollagen type I, alpha SMA (marker for myofibroblast phenotype) and migratory properties. These effects were associated with significantly increased activity of AMPK, a known inhibitor of fibrosis, in vivo and in vitro, and abrogated in NCF transfected with AMPKα1/α2 siRNA. The reversal of myocardial fibrosis by R in DKO mice was accompanied with improved LV function assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).We conclude that Rosuvastatin reverses LV remodelling and improves LV relaxation through anti-fibrotic effects rather than direct effects on cardiomyocytes, through activation of AMPK.
- © 2012 by American Heart Association, Inc.