title: Simvastatin activates the PPARγ-dependent pathway to prevent left ventricular hypertrophy associated with inhibition of RhoA signaling.
abstract: Left ventricular hypertrophy is an independent risk factor for major adverse cardiovascular events. Statins have positive effects on this condition; however, the mechanisms are incompletely understood. In this study, we examined whether the effect of simvastatin on left ventricular hypertrophy can be mediated with the peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway in rabbits with nonischemic heart failure (HF). We induced aortic insufficiency and constriction in 48 rabbits and divided them equally into control, HF, and HF with simvastatin therapy (HF-SIM) groups. The HF-SIM group was given 10 mg/kg/d of simvastatin. We echocardiographically measured baseline and 8-week cardiac structure and function, and we used Western blot, polymerase chain reaction, and electrophoretic analytic techniques to evaluate messenger RNA expression and protein expression and activity. In comparison with the HF group, the HF-SIM rabbits had an increased ejection fraction and decreased left ventricular mass index, interventricular septal thickness, ventricular posterior-wall thickness, and collagen volume fraction. Moreover, the messenger RNA and protein expression of PPARγ in the HF-SIM rabbits were significantly higher than those in the HF rabbits; and the activity and expression of nuclear factor-κB subunit p65, RhoA, and Rho GTPase were significantly lower. Our results indicate that simvastatin therapy attenuates the PPARγ-dependent pathway in association with the inhibition of RhoA and Rho GTPase signaling to inhibit nuclear factor-κB activation, thus preventing the development of left ventricular hypertrophy and fibrosis in rabbits with nonischemic heart failure.
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Soochow University, Suzhou 215006, People's Republic of China. nkzc75@163.com
authors.forename: Cao
authors.initials: C
authors.lastname: Zou
authors.forename: Hongtao
authors.initials: H
authors.lastname: Qi
authors.forename: Zhi-hua
authors.initials: ZH
authors.lastname: Liu
authors.forename: Lianhua
authors.initials: L
authors.lastname: Han
authors.forename: Caiming
authors.initials: C
authors.lastname: Zhao
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014463:Ultrasonography; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047495:PPAR gamma; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D019821:Simvastatin; D020742:rhoA GTP-Binding Protein
keywords: Disease models, animal; NF-kappa B/metabolism; PPAR gamma/drug effects/metabolism; heart failure/drug therapy; heart ventricles/drug effects; hypertrophy, left ventricular/physiopathology/prevention & control; rhoA GTP-binding protein; simvastatin; ventricular function, left/drug effects