Mitophagy Is Required for Acute Cardioprotection by Simvastatin

Abstract

Aims: We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. Results: HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q 10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Innovation and Conclusion: Acute simvastatin treatment suppresses mTOR signaling and triggers Parkindependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy.

Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction

“…Indeed, statins have been reported to decrease membrane cholesterol levels in various cell types. 35,36 Moreover, mevalonate, the cholesterol intermediate just downstream of HMG-CoA, reverses statin-induced inhibition of MTOR signaling, 37,38 indicating that HMGCR inhibition is required for the suppression of MTOR activity. However, additional studies are needed to confirm that statins reduce membrane cholesterol level in hepatocytes and that statin-induced autophagy and gluconeogenesis are mediated through the suppression of MTOR activity.…”

Untangling Autophagy Measurements

“…The specific targeting of mitochondria for autophagic disposal during I/R insult is an important element of cardioprotection 21, 22 . Because mitochondrial autophagy is a major pathway for turnover of mitochondria, it is important to be able to monitor mitophagy.…”

“…They found that the cell death was prevented by cyclosporine A but not that pan-caspase inhibitor ZVAD, suggesting that the mitochondrial permeability transition pore was responsible for triggering necrotic cell death 16 . Other studies have shown the importance of clearing damaged mitochondria to reduce ischemia/reperfusion injury 2, 15, 21–23 . Postconditioning was also shown to restore autophagic flux during reperfusion, whereas inhibition of flux (with chloroquine) abolished the protective effects of sevoflurane postconditioning 24 .…”

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

“…[18][19][20] The underlying mechanisms for these cardioprotective effects remain unclear. Given that statins induce autophagy in cancer cells, as well as in some normal cells, [21][22][23] there is reason to believe that statin-mediated cardiac benefits may be through autophagy-related mechanisms.…”