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Int J Cardiol. 2017 Feb 1;228:543-552. doi: 10.1016/j.ijcard.2016.11.247. Epub 2016 Nov 14.

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.

Author information

1
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.
2
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
3
Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
4
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
5
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.
6
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.
7
Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: linrock@ms26.hinet.net.

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/f mice, 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/f mice 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.

CONCLUSION:

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.

KEYWORDS:

Aging; Apoptosis; Contractile dysfunction; Endoplasmic reticulum stress; Sirtuin 1

PMID:
27875732
DOI:
10.1016/j.ijcard.2016.11.247
[Indexed for MEDLINE]

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