Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt

Mullen, Peter; Zahno, Anja; Lindinger, Peter W.; Maseneni, Swarna; Felser, Andrea; Krähenbühl, Stephan; Brecht, Karin

doi:10.1016/j.bbamcr.2011.07.019

Cited by 69 publications

(74 citation statements)

References 46 publications

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“…Our findings are difficult to reconcile with previous reports linking Akt to cardioprotection (30), but the differences may be related to the duration of statin administration. Dephosphorylation of Akt in statintreated C2C12 myotubes was previously described (35). Our studies further revealed the upregulation of autophagy through ULK1.…”

Section: Discussionsupporting

confidence: 58%

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Mitophagy Is Required for Acute Cardioprotection by Simvastatin

Andres

Hernandez²,

Lee³

et al. 2014

Antioxidants & Redox Signaling

169

124

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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.

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Section: Discussionsupporting

confidence: 58%

“…Statins have been reported to decrease superoxide production, in part through downregulation of nicotinamide adenine dinucleotide phosphate oxidase activity (8). Statins also are reported to improve mitochondrial function (26,51), although they have deleterious effects in skeletal muscle (19,27,35,36).…”

mentioning

confidence: 99%

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

Andres

Hernandez²,

Lee³

et al. 2014

Antioxidants & Redox Signaling

169

124

View full text Add to dashboard Cite

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“…Previous work from our group suggested that simvastatin-induced myotoxicity might be related to inhibition of the phosphorylation and thereby activation of AKT [14]. As shown in Fig.…”

Section: Introductionmentioning

confidence: 84%

The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity

Bonifacio

Sanvee

Bouitbir

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Statins are drugs that lower blood cholesterol levels and reduce cardiovascular morbidity and mortality. They are generally well-tolerated, but myopathy is a potentially severe adverse reaction of these compounds. The mechanisms by which statins induce myotoxicity are not completely understood, but may be related to inhibition of the AKT signaling pathway. The current studies were performed to explore the down-stream effects of the statin-associated inhibition of AKT within the AKT signaling pathway and on myocyte biology and morphology in C2C12 myotubes and in mice in vivo. We exposed C2C12 myotubes to 10 μM or 50 μM simvastatin, atorvastatin or rosuvastatin for 24 h. Simvastatin and atorvastatin inhibited AKT phosphorylation and were cytotoxic starting at 10 μM, whereas similar effects were observed for rosuvastatin at 50 μM. Inhibition of AKT phosphorylation was associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E-binding protein 1 and FoxO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of C2C12 myotubes. Furthermore, impaired AKT phosphorylation was associated with activation of caspases and PARP, reflecting induction of apoptosis. Similar findings were detected in skeletal muscle of mice treated orally with 5 mg/kg/day simvastatin for 3 weeks. In conclusion, this study highlights the importance of the AKT/mTOR signaling pathway in statin-induced myotoxicity and reveals potential drug targets for treatment of patients with statin-associated myopathies.

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“…Our data agree with previous experimental and human studies. Indeed, simvastatin causes a decrease in mitochondrial respiration in primary mouse myocytes and induces myotube atrophy and cell loss associated with impaired mitochondrial respiratory capacity, mitochondrial oxidative stress and apoptosis in primary human skeletal myotubes (24).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Syndrome and Chronic Simvastatin Therapy Enhanced Human Cardiomyocyte Stress before and after Ischemia- Reperfusion in Cardio-Pulmonary Bypass Patients

Corsetti

Pasini²,

Ferrari-Vivaldi³

et al. 2012

Int J Immunopathol Pharmacol

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The first two authors contributed equally to the work Metabolic syndrome (MetS) is a set of metabolic alterations including high levels of low-density lipoprotein (LDL), which increase the risk of cardiomyopathy often leading to surgery. Despite inducing myopathy, statins are widely used to lower LDL. Cardiopulmonary bypass (Cpb) causes oxidative stress and metabolic injury, altering mitochondrial expression (Grp75) and endoplasmic reticulum (Grp78) chaperones, apoptotic enzymes (Bcl2 family) and increasing cardiomyocyte lipidllipofuscin storage. We believe that cardiomyocytes from patients with MetS may be more sensitive to surgical stress, in particular after simvastatin therapy (MetS+Stat). The study group included ten patients with MetS, ten patients with Mets+Stat and ten healthy subjects. Myocardial biopsies were obtained both before and after-Cpb. Grp75, Grp78, Bax, Bcll, lipids, lipofuscin and fibrosis were evaluated by immunol histochemistry. MetS cardiomyocytes had higher Grp75, Bax, fibrosis and lipofuscin. MetS+Stat had lower Grp75 and higher Grp78 expressions, high Bax, fewer fibrosis and higher lipofuscin content. Cpb did not vary the fibrosis and lipidsllipofuscin content, although it influenced the chaperones and Bax expression in all groups. These changes were more profound in patients with MetS and even more so in patients with MetS+Stat. The results suggest that MetS and MetS+Stat cardiomyocytes were more highly stressed after-Cpb, Interestingly, simvastatin caused high stress even before-Cpb.Metabolic syndrome (MetS) is a cluster ofvarious clinical features. This syndrome increases the risk of metabolic cardiomyopathy and coronary artery disease (CAD). CAD can cause myocardial ischemia requiring surgical myocardial revascularization (1) and causes intrinsic metabolic and structural cardiomyocyte damage. Many drugs are currently used to treat MetS, both to reduce risk factors and to

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Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt

Cited by 69 publications

References 46 publications

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity

Metabolic Syndrome and Chronic Simvastatin Therapy Enhanced Human Cardiomyocyte Stress before and after Ischemia- Reperfusion in Cardio-Pulmonary Bypass Patients

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