Abstract 314: Infarct Size Reduction by Statins Requires Parkin and Mitophagy

Abstract

The cardioprotective effects of statins are well known yet the mechanism is unclear. Previously we showed that autophagy is required for cardioprotection from ischemia/reperfusion injury. More recently, we reported that ischemic preconditioning involves Parkin-mediated mitophagy. We hypothesized that the molecular basis of statin-mediated cardioprotection may involve mitochondrial quality control through mitophagy. HL-1 cardiomyocytes treated with simvastatin for 24hr exhibited diminished Akt/mTOR signaling, increased activation of ULK1, and upregulation of autophagy (n=3, p<0.05). Similar findings were obtained in cardiac tissue in mice 4hr after i.p. administration of simvastatin. Mevalonate addition abolished statin’s effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of HMG-CoA reductase. Statin treatment in HL-1 cells triggered mitochondrial fragmentation, translocation of Parkin and p62/SQSTM1 to the mitochondria followed by mitophagy. To establish the requirement for statin-mediated mitophagy in cardioprotection, we investigated the ability of statins to reduce infarct size in Parkin knockout (KO) mice. While statin treatment reduced infarct size from 55% of area at risk to 30% in wild type mice, it had no protective benefit in Parkin KO mice (n=4-6, p<0.05). These findings indicate that cardioprotection by HMG-CoA reductase inhibitors involves suppression of mTOR signaling and induction of Parkin-dependent mitophagy. Figure: Statin-induced cardioprotection against I/R injury: solid bars/diamonds = wild-type; open bars/diamonds = Parkin knockout mice.