Abstract
Lipotoxic cardiomyopathy is caused by myocardial lipid accumulation and often occurs in patients with diabetes and obesity. This study investigated the effects of β-lapachone (β-lap), a natural compound that activates Sirt1 through elevation of the intracellular NAD+ level, on acyl CoA synthase (ACS) transgenic (Tg) mice, which have lipotoxic cardiomyopathy. Oral administration of β-lap to ACS Tg mice significantly attenuated heart failure and inhibited myocardial accumulation of triacylglycerol. Electron microscopy and measurement of mitochondrial complex II protein and mitochondrial DNA revealed that administration of β-lap restored mitochondrial integrity and biogenesis in ACS Tg hearts. Accordingly, β-lap administration significantly increased the expression of genes associated with mitochondrial biogenesis and fatty acid metabolism that were down-regulated in ACS Tg hearts. β-lap also restored the activities of Sirt1 and AMP-activated protein kinase (AMPK), the two key regulators of metabolism, which were suppressed in ACS Tg hearts. In H9C2 cells, β-lap-mediated elevation of AMPK activity was retarded when the level of Sirt1 was reduced by transfection of siRNA against Sirt1. Taken together, these results indicate that β-lap exerts cardioprotective effects against cardiac lipotoxicity through the activation of Sirt1 and AMPK. β-lap may be a novel therapeutic agent for the treatment of lipotoxic cardiomyopathy.
Highlights
Myocardial metabolic abnormalities, which occur in response to various factors including obesity and diabetes, are significant risk factors for heart failure [1,2]
The fuel used in myocardial metabolism switches from fatty acids (FAs) to glucose in pathological conditions including cardiac hypertrophy, ischemia, myocardial infarction, and heart failure [5,6,7]
We investigated the effects of b-lap administration in transgenic (Tg) mice overexpressing acyl CoA synthase (ACS), which have severe lipotoxic cardiomyopathy due to excess import of FAs into cardiomyocytes [21]
Summary
Myocardial metabolic abnormalities, which occur in response to various factors including obesity and diabetes, are significant risk factors for heart failure [1,2]. We show that oral administration of b-lap to ACS Tg mice reduced lipid accumulation in the heart and attenuated lipotoxicity-induced heart failure through increasing Sirt1 and AMPK activities. We tested whether b-lap affects mitochondrial integrity and activity in the heart of ACS Tg mice.
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