Downregulation of Sirt1 as aging change in advanced heart failure

Tse Min Lu, Jia Yun Tsai, Yen Chung Chen, Chun Yang Huang, Hung Lung Hsu, Chi Feng Weng, Chun Che Shih, Chiao Po Hsu

Research output: Contribution to journalArticle

45 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish
Article number57
JournalJournal of Biomedical Science
Volume21
Issue number1
DOIs
Publication statusPublished - Jun 9 2014
Externally publishedYes

Fingerprint

Sirtuin 1
Down-Regulation
Heart Failure
Aging of materials
Cardiac Myocytes
Molecules
AMP-Activated Protein Kinases
Oxidative stress
Cell Survival
Oxidative Stress
Up-Regulation
Antioxidants
Cells
In Situ Nick-End Labeling
Reperfusion Injury
Superoxide Dismutase
Cell death
Cell Death
Machinery

Keywords

  • Aging
  • Heart failure
  • Sirt1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

Cite this

Downregulation of Sirt1 as aging change in advanced heart failure. / Lu, Tse Min; Tsai, Jia Yun; Chen, Yen Chung; Huang, Chun Yang; Hsu, Hung Lung; Weng, Chi Feng; Shih, Chun Che; Hsu, Chiao Po.

In: Journal of Biomedical Science, Vol. 21, No. 1, 57, 09.06.2014.

Research output: Contribution to journalArticle

Lu, Tse Min ; Tsai, Jia Yun ; Chen, Yen Chung ; Huang, Chun Yang ; Hsu, Hung Lung ; Weng, Chi Feng ; Shih, Chun Che ; Hsu, Chiao Po. / Downregulation of Sirt1 as aging change in advanced heart failure. In: Journal of Biomedical Science. 2014 ; Vol. 21, No. 1.
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AU - Lu, Tse Min

AU - Tsai, Jia Yun

AU - Chen, Yen Chung

AU - Huang, Chun Yang

AU - Hsu, Hung Lung

AU - Weng, Chi Feng

AU - Shih, Chun Che

AU - Hsu, Chiao Po

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AB - 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. Conclusion: 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.

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