title: Sirtuin 1 protects the aging heart from contractile dysfunction mediated through the inhibition of endoplasmic reticulum stress-mediated apoptosis in cardiac-specific Sirtuin 1 knockout mouse model.
abstract: BACKGROUND
  The longevity regulator Sirtuin 1 is an NAD+-dependent histone deacetylase that regulates endoplasmic reticulum stress and influences cardiomyocyte apoptosis during cardiac contractile dysfunction induced by aging. The mechanism underlying Sirtuin 1 function in cardiac contractile dysfunction related to aging has not been completely elucidated.
  
  
  METHODS
  We evaluated cardiac contractile function, endoplasmic reticulum stress, apoptosis, and oxidative stress in 6- and 12month-old cardiac-specific Sirtuin 1 knockout (Sirt1-/-) and control (Sirt1f/f) mice using western blotting and immunohistochemistry. Mice were injected with a protein disulphide isomerase inhibitor. For in vitro analysis, cultured H9c2 cardiomyocytes were exposed to either a Sirtuin 1 inhibitor or activator, with or without a mitochondrial inhibitor, to evaluate the effects of Sirtuin 1 on endoplasmic reticulum stress, nitric oxide synthase expression, and apoptosis. The effects of protein disulphide isomerase inhibition on oxidative stress and ER stress-related apoptosis were also investigated.
  
  
  RESULTS
  Compared with 6-month-old Sirt1f/fmice, marked impaired contractility was observed in 12-month-old Sirt1-/-mice. These findings were consistent with increased endoplasmic reticulum stress and apoptosis in the myocardium. Measures of oxidative stress and nitric oxide synthase expression were significantly higher in Sirt1-/-mice compared with those in Sirt1f/fmice at 6months. In vitro experiments revealed increased endoplasmic reticulum stress-mediated apoptosis in H9c2 cardiomyocytes treated with a Sirtuin 1 inhibitor; the effects were ameliorated by a Sirtuin 1 activator. Moreover, consistent with the in vitro findings, impaired cardiac contractility was demonstrated in Sirt1-/-mice injected with a protein disulphide isomerase inhibitor.
  
  
  CONCLUSIONS
  The present study demonstrates that the aging heart is characterized by contractile dysfunction associated with increased oxidative stress and endoplasmic reticulum stress and Sirtuin 1 might have the ability to protect the aging hearts from the inhibition of endoplasmic reticulum-mediated apoptosis.
authors.affiliation: Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yu-Juei
authors.initials: YJ
authors.lastname: Hsu
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Che
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Superintendent's Office, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chien-Sung
authors.initials: CS
authors.lastname: Tsai
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: linrock@ms26.hinet.net.
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Lin
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
chemical_list: D004247:DNA; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Aging; Apoptosis; Contractile dysfunction; Endoplasmic reticulum stress; Sirtuin 1