title: Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice.
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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Kawashima
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Inuzuka
authors.forename: Junji
authors.initials: J
authors.lastname: Okuda
authors.forename: Takao
authors.initials: T
authors.lastname: Kato
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Niizuma
authors.forename: Yodo
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Akira
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Michiko
authors.initials: M
authors.lastname: Narazaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matsuda
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D005786:Gene Expression Regulation; D054144:Heart Failure, Diastolic / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D045222:Electron Transport Chain Complex Proteins; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D056564:Sirtuin 1