title: Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure.
abstract: SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), is an NAD(+)-dependent protein deacetylase that plays a critical role in the regulation of vascular function. The current study aims to investigate the functional significance of deacetylase activity of SIRT1 in heart. Here we show that the early postnatal hearts expressed the highest level of SIRT1 deacetylase activity compared to adult and aged hearts. We generated transgenic mice with cardiac-specific expression of a dominant-negative form of the human SIRT1 (SIRT1H363Y), which represses endogenous SIRT1 activity. The transgenic mice displayed dilated atrial and ventricular chambers, and died early in the postnatal period. Pathological, echocardiographic and molecular phenotype confirmed the presence of dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed a greater abundance of apoptotic nuclei in the hearts of transgenic mice. Furthermore, we show that cardiomyocyte apoptosis caused by suppression of SIRT1 activity is, at least in part, due to increased p53 acetylation and upregulated Bax expression. These results indicate that dominant negative form of SIRT1 (SIRT1H363Y) overexpression in mouse hearts causes cardiomyocyte apoptosis and early-onset heart failure, suggesting a critical role of SIRT1 in preserving normal cardiac development during the early postnatal period.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
authors.forename: WenLi
authors.initials: W
authors.lastname: Mu
authors.forename: QingJun
authors.initials: Q
authors.lastname: Zhang
authors.forename: XiaoQiang
authors.initials: X
authors.lastname: Tang
authors.forename: WenYan
authors.initials: W
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: YunBiao
authors.initials: Y
authors.lastname: Lu
authors.forename: HongLiang
authors.initials: H
authors.lastname: Li
authors.forename: YuSheng
authors.initials: Y
authors.lastname: Wei
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: ZhiGang
authors.initials: Z
authors.lastname: She
authors.forename: HouZao
authors.initials: H
authors.lastname: Chen
authors.forename: DePei
authors.initials: D
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D017668:Age of Onset; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D005799:Genes, Dominant; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1