title: Downregulation of Sirt1 as aging change in advanced heart failure.
abstract: BACKGROUND
  In congestive heart failure the balance between cell death and cell survival in cardiomyocytes is compromised. Sirtuin 1 (Sirt1) activates cell survival machinery and has been shown to be protective against ischemia/reperfusion injury in murine heart. The role of Sirt1 in heart failure, especially in human hearts is not clear.
  
  
  RESULTS
  The expression of Sirt1 and other (associated) downstream molecules in human cardiomyocytes from patients with advanced heart failure was examined. Sirt1 was down-regulated (54.92% ± 7.80% in advanced heart failure samples compared with healthy control cardiomyocytes). The modulation of molecules involved in cardiomyocyte survival and death in advanced heart failure were also examined. The expression of Mn-superoxide dismutase and thioredoxin1, as well as an antiapoptotic molecule, Bcl-xL, were all significantly reduced in advanced heart failure cardiomyoctes (0.71 ± 0.02-fold, 0.61 ± 0.05-fold, and 0.53 ± 0.08-fold vs. control, respectively); whereas the expression of proapoptotic molecule Bax was significantly increased (1.62 ± 0.18-fold vs. control). Increased TUNEL-positive number of cardiomyocytes and oxidative stress, confirmed by 8-hydorxydeoxyguanosine staining, were associated with advanced heart failure. The AMPK-Nampt-Sirt1 axis also showed inhibition in advanced heart failure in addition to severely impaired AMPK activation. Increased p53 (acetyl form) and decreased FoxO1 translocation in the nucleus may be the mechanism of down-regulation of antioxidants and up-regulation of proapoptotic molecules due to low expression of Sirt1.
  
  
  CONCLUSIONS
  In advanced heart failure, low Sirt1 expression, like aging change may be a significant contributing factor in the downregulation of antioxidants and upregulation of proapoptotic molecules through the p53, FoxO1, and oxidative stress pathways.
authors.forename: Tse-Min
authors.initials: TM
authors.lastname: Lu
authors.forename: Jia-Yun
authors.initials: JY
authors.lastname: Tsai
authors.forename: Yen-Chung
authors.initials: YC
authors.lastname: Chen
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Hung-Lung
authors.initials: HL
authors.lastname: Hsu
authors.forename: Chi-Feng
authors.initials: CF
authors.lastname: Weng
authors.forename: Chun-Che
authors.initials: CC
authors.lastname: Shih
authors.affiliation: National Yang-Ming University, Institute of Clinical Medicine, School of Medicine, Taipei, Taiwan. chiaopo@ms39.hinet.net.
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D056564:Sirtuin 1 / Q000096:biosynthesis*; D013482:Superoxide Dismutase / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C074639:Foxo1 protein, rat; D013482:Superoxide Dismutase; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1