Abstract 11089: Constitutive SIRT1 Overexpression Impairs Mitochondrial Function in Mice
Background: Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD+-dependent protein deacetylase, and is a homolog of yeast sir2 gene. Sir2 plays a critical role in life span regulation in yeast. In mammals, SIRT1 is important in the regulation of cellular energy metabolism. We tested the hypothesis that SIRT1 was important in cardiac energy metabolism.
Methods and Results: Overexpression of SIRT1 in cultured cardiac myocytes modified the expression of genes related to mitochondrial function. To examine the role of SIRT1 in cardiac energy metabolism in vivo, we created transgenic mice overexpressing SIRT1 in a heart-specific manner and analyzed the metabolic profile of the heart. Overexpression of SIRT1 impaired cardiac function in a transgene dosage-dependent manner, and caused heart failure in a transgenic line expressing the highest amount of SIRT1. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased in a manner dependent on SIRT1 gene dosage. The respiration of isolated mitochondria was decreased by 75% in a SIRT1 transgenic line that did not develop heart failure. Changes in mitochondrial function and morphology were associated with decreased expression of genes involved in fatty acid metabolism and mitochondrial function such as nuclear respiratory factor-1 (NRF-1), medium-chain acyl coenzyme A dehydrogenase (MCAD), NADH dehydrogenase 1 alpha subcomplex 9 (α-s9), succinate dehydrogenase complex subunit B (SDHB), and cytochrome c oxidase VIIa1 (Cox7a1). Unexpectedly, markers of oxidative stress were decreased in SIRT1 transgenic mice.
Conclusion: Constitutive overexpression of SIRT1 reduced mitochondrial function and impaired cardiac function in mice.
- © 2010 by American Heart Association, Inc.