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Metoprolol and cardiac carnitine palmitoyltransferase-1 : unravelling a complex interaction in normal and diabetic hearts Sharma, Vijay

Abstract

Diabetic cardiomyopathy may be initiated or compounded by the heavy reliance of the heart on fatty acids and ketones as metabolic fuels. β-blockers have been proposed to inhibit fatty acid oxidation by decreasing the activity of the enzyme carnitine palmitoyltransferase-1 (CPT-1). By inhibiting fatty acid oxidation, β-blockers could improve myocardial efficiency and ameliorate the cytoplasmic accumulation of toxic fatty acid and glucose intermediates. In this study, we investigated whether metoprolol improves cardiac function and inhibits fatty acid oxidation in the streptozotocin (STZ) diabetic rat, a model of poorly controlled type 1 diabetes. The animals were injected with 60 mg/kg STZ and were euthanized six weeks following the induction of diabetes. We investigated the effects of chronic metoprolol treatment (75 mg/kg/day), and acute metoprolol perfusion on cardiac function, substrate utilization and three major systems of CPT-1 regulation: malonyl CoA levels, CPT-1 transcription and covalent modifications (phosphorylation, nitrosylation, glutathiolation, nitration). Chronic metoprolol treatment improved cardiac function in the diabetic heart. Whereas, chronic metoprolol treatment increased fatty acid oxidation in control hearts but decreased it in diabetic hearts, acute metoprolol perfusion always inhibited fatty acid oxidation. Metoprolol lowered malonyl CoA levels in control hearts, and both acute metoprolol perfusion and chronic metoprolol treatment led to decreased CPT-1 maximum activity and decreased CPT-1 malonyl CoA sensitivity. CPT-1 sensitivity was increased by calcium/calmodulin-dependent protein kinase phosphorylation and decreased by protein kinase A-dependent phosphorylation in vitro. CPT-1 activity was inhibited by nitrosylation and glutathiolation, and stimulated by nitration in vitro. Chronic metoprolol treatment decreased the binding and coactivation of peroxisome-proliferator receptor-γ coactivator 1-α (PGC-1α) and peroxisome-proliferator receptor-α (PPAR-α), and also increased the binding of the repressor protein upstream stimulatory factor-2 (USF-2). In conclusion, metoprolol inhibited fatty acid oxidation, and acted partly by regulating malonyl CoA levels and partly by modulating the activity and malonyl CoA sensitivity of CPT-1 itself. The effects of metoprolol on CPT-1 were mediated acutely by covalent modifications and chronically by inhibition of the transcriptional complex that induces CPT-1 expression.

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