Studies On The Molecular Mechanism Of Rapamycin's Attenuation Of Post-infarction Ventricular Remodeling

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. mTOR inhibitor--rapamycin and it's analogs are currently being tested in several clinical trials. Akt/mTOR/S6K1(protein kinase B/ Mammalian target of rapamycin/ P70 ribosomal protein S6 kinase) signaling plays a important role in cardiac hypertrophy and previous studies have showed rapamycin had therapeutic and prophylactic effects on load-induced pathophysiologic hypertrophy and improved cardiac function. But it's effects in myocardial infarction(MI) is unclear. The aim of present study was to examine whether rapamycin have protective effects in MI and explore it's mechanism.First, to exclude the possibility that inhibition of mTOR may be detrimental to cardiac function, mice were administered rapamycin (10mg/kg/d,intraperitioneally) or drug vehicle for 10 weeks. We found there was no difference in cardiac function and heart weight/body weight between rapamycin group and vehicle group. Then we examined whether Akt/mTOR/S6K1 signaling was activated in response to acute myocardial infarction. The level of phospho-S6k T389,Akt-S473 and Akt-T308 were increased especially for phospho-S6k T389 from 2 days after MI and were similar to baseline levels 7 days after MI. We hypothesized S6k may play an important role in cardiac remodelling after MI. Treatment with rapamycin inhibited phosphorylation activity of P-S6k and P-S6 obviously. We administered rapamycin with different dosage and duration to mice subjected to left coronary artery ligation which resulted in transmural infarction. The results showed rapamycin lessened left ventricular dilation and fibrotic area, ameliorated cardiac function. The effects was the same in different dosage group but was obvious in longer duration group. We found rapamycin suppressed S6K1 phosphorylation in hearts and concurrently decreased the phosphorylation of Akt at Ser473, but increased the phosphorylation of Akt at Thr308 obviously. Deletion of PDK1 (3-phosphoinositide dependentproteinkinase-1) in cardiomyocyte prevented rapamycin's protection against MI because the enhancement of Akt T308 phosphorylation in heart was abrogated.These results demonstrated that rapamycin rendered beneficial effects on left ventricular function and alleviated adverse remodeling following acute MI in mice through suppressing S6K activation and enhancing Akt (at Thr308) signaling, suggesting rapamycin's therapeutic value in the treatment of human MI.