Long‐term atorvastatin treatment inhibited pro‐survival signaling, reduced mitochondrial function and altered ultrastructural integrity in cardiac myocytes (1095.6)

Abstract

Introduction: Statins are widely used to lower low‐density lipoprotein cholesterol (LDL‐C) for prevention of cardiovascular disease. The FDA warns that statins may induce skeletal muscle side effects. Skeletal muscle biopsies from patients with statin myopathy showed defects in mitochondrial ultrastructure. Impaired mitochondrial function was postulated as a key cause of statin‐induced myopathy. Long‐term statin effects on cardiac muscle are currently unclear.Methods and Results: Neonatal cardiac myocytes were treated with either atorvastatin (lipophilic) or pravastatin (hydrophilic) for up to 48 hours (both at 1‐10 μM). Atorvastatin, but not pravastatin, inhibited RhoA activation, reduced mTOR/AKT signaling, and induced apoptosis. Further, atorvastatin treatment reduced protein expression of caveolin, dystrophin and epidermal growth factor receptor in cardiac myocytes. Both statins induced ER stress responses, but only atorvastatin increased CHOP initiated apoptotic cell death. Assessment of mitochondrial function after 48 hours of statin therapy revealed reduced oxygen consumption rates in atorvastatin treated cardiac myocytes, when compared to pravastatin or vehicle treated cells. The extracellular acidification rate profile was unchanged between groups at all time points. When mice underwent long‐term atorvastatin or pravastatin (5mg/kg/day for 7 months) treatment, both statins reduced LDL‐C, but only atorvastatin increased creatine kinase serum levels. Atorvastatin therapy in mice altered mitochondrial ultrastructure and induced protein aggregate formation in the heart. Atorvastatin, but not pravastatin, increased mortality in cardiomyopathic mice, when compared to vehicle treated controls.Conclusion: Atorvastatin reduced mitochondrial function, altered cardiac ultrastructure and induced apoptosis in cardiac myocytes. Our data suggest that long‐term atorvastatin treatment impaired mitochondrial integrity in cardiac muscle.