title: Mitophagy is required for acute cardioprotection by simvastatin.
abstract: OBJECTIVE
  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 Q10 (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.
  
  
  CONCLUSIONS
  Acute simvastatin treatment suppresses mTOR signaling and triggers Parkin-dependent 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.
authors.affiliation: Donald P. Shiley BioScience Center, San Diego State University , San Diego, California.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Andres
authors.forename: Genaro
authors.initials: G
authors.lastname: Hernandez
authors.forename: Pamela
authors.initials: P
authors.lastname: Lee
authors.forename: Chengqun
authors.initials: C
authors.lastname: Huang
authors.forename: Eric P
authors.initials: EP
authors.lastname: Ratliff
authors.forename: Jon
authors.initials: J
authors.lastname: Sin
authors.forename: Christine A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Marichris V
authors.initials: MV
authors.lastname: Damasco
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002460:Cell Line; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D051379:Mice; D063306:Mitophagy / Q000187:drug effects* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000008:administration & dosage / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; C546843:mTOR protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse
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