Mitophagy is required for acute cardioprotection by simvastatin
| Autor: | Marichris V. Damasco, Jon Sin, Chengqun Huang, Eric P. Ratliff, Christine A Thornton, Allen M. Andres, Roberta A. Gottlieb, Pamela Lee, Genaro Hernandez |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Simvastatin Statin Cardiotonic Agents Physiology medicine.drug_class Clinical Biochemistry Biology Pharmacology Protein Serine-Threonine Kinases Biochemistry Parkin Cell Line Mice Internal medicine Mitophagy medicine Autophagy Animals Autophagy-Related Protein-1 Homolog Humans Myocytes Cardiac cardiovascular diseases Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway General Environmental Science Cardioprotection Forum Original Research Communications TOR Serine-Threonine Kinases nutritional and metabolic diseases Cell Biology Endocrinology Reperfusion Injury General Earth and Planetary Sciences lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Antioxidantsredox signaling. 21(14) |
| ISSN: | 1557-7716 |
| Popis: | 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 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. Innovation and Conclusion: 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. Antioxid. Redox Signal. 21, 1960–1973. |
| Databáze: | OpenAIRE |
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