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. 2011 Dec;51(6):1026-36.
doi: 10.1016/j.yjmcc.2011.09.013. Epub 2011 Sep 22.

Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice

Tsuneaki Kawashima  1 , Yasutaka Inuzuka, Junji Okuda, Takao Kato, Shinichiro Niizuma, Yodo Tamaki, Yoshitaka Iwanaga, Akira Kawamoto, Michiko Narazaki, Tetsuya Matsuda, Souichi Adachi, Genzou Takemura, Toru Kita, Takeshi Kimura, Tetsuo Shioi
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Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice

Tsuneaki Kawashima et al. J Mol Cell Cardiol. 2011 Dec.

Abstract

Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD(+)-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.

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