Simvastatin prevents cardiac hypertrophy in vitro and in vivo via JAK/STAT pathway.
Simvastatin (SIM), a HMG-CoA reductase inhibitor, has therapeutic effects that are not limited to cholesterol reduction. In this study, we investigated the change in the cell surface area and protein content of cultured rat cardiomyocytes on exposure to cardiotrophin-1 (CT-1), a cytokine involved in the growth and survival of cardiac cells, plus SIM, and thus confirmed that SIM ameliorated cardiomyocyte hypertrophy induced by CT-1. We also showed that SIM attenuated cardiac hypertrophy in rats with pressure overload due to abdominal aortic constriction by measuring such parameters as systolic blood pressure, ratio of heart weight to body weight and ratio of left ventricular weight to body weight in rats as well as cross-sectional area of cardiomyocytes. Western blot analysis indicated that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway was involved in the mechanisms underlying the in vitro and in vivo inhibitory effects of SIM on cardiac hypertrophy. Moreover, the effect of SIM amelioration on CT-1-induced cultured cardiomyocyte hypertrophy might be related to the change in angiotensinogen (AGT) mRNA expression, as evidenced by RT-PCR analysis, and the subsequent alteration in angiotensin II (Ang II) levels. The results of our study provide further evidence that SIM, like other HMG-CoA reductase inhibitors, is a promising drug for prevention and treatment of cardiac hypertrophy.
Liu
Juan
J
Institute for Nautical Medicine, Nantong University, Nantong, Jiangsu Province 226001, People's Republic of China.
Shen
Qin
Q
Wu
Yang
Y
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000517:prevention & control*; D048429:Cell Size / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D053612:Janus Kinases / Q000096:biosynthesis*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000096:biosynthesis*; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050791:STAT Transcription Factors; D019821:Simvastatin; C092073:cardiotrophin 1; D053612:Janus Kinases