Session Speaker

Activation of Sirtuins by β-Lapachone Prevents Cardiac Hypertrophy and Heart Failure
Woo Jin Park, Dong Kwon Yang, Tae Hwan Kwak
Reublic of Korea

Calorie restriction (CR) is known to extend life spans in a wide spectrum of organisms, and exert beneficial effects in age-related metabolic diseases. Accumulating data have indicated that CR mediates its salutary effects through activation of sirtuin family proteins. Sirtuins are a group of proteins related to yeast Silence information regulator 2 (Sir2), which is an NAD⁺-dependent class III histone deacetylase and mono-ADP-ribosyltransferase, and plays critical roles in a variety of cellular processes including gene silencing, longevity, and DNA damage repair. Among the seven mammalian sirtuins (Sirt1-Sirt7), Sirt1 is the closest homologue of yeast Sir2.

Considering arrays of potential benefits of sirtuin activation, the development of pharmacological activators of sirtuins has intensively been sought after. Well known such a compound is resveratrol, a polyphenol found in grapes. Studies in animal models suggested that resveratrol and related compounds may be useful for treatment of metabolic diseases including obesity and diabetes. Based on the fact that sirtuin activity is sensitive to the cellular [NAD⁺]/[NADH] ratio, we hypothesized that pharmacological elevation of the cellular [NAD⁺]/[NADH] ratio could be a strategy to increase sirtuin activity. Therefore, we sought to test this hypothesis using a natural compound, β-lapachone (β-lap), which is a cofactor of a cytosolic enzyme NAD(P)H:quinine oxidoreductase (NQO1). β-lap was shown to accelerate NAD(P)H oxidation by NQO1 in a futile oxidation/reduction cycle and thus elevate the cellular [NAD⁺]/[NADH] ratio.

We show here that oral administration of β-lap to mice indeed increased the sirtuin activity in the hearts, as demonstrated by increased NAD⁺ contents and decreased acetylation of FOXO, P53, and PARP-1. We will present compelling lines evidence supporting that β-lap significantly attenuated pressure overload-induced cardiac hypertrophy and heart failure, and myocardial infarction in mice through the sirtuin activity. While the mitochondria in cardiomyocytes were rapidly disintegrated by pressure overload, they remained intact in the β-lap fed mice under the same conditions. The conservation of mitochondrial integrity was paralleled with increased fatty acid utilizations in the β-lap fed mice, consistent with a notion that a shift in a metabolism is a cause for development of heart failure. We suggest that β-lap is a promising candidate compound for treatment of heart failure.