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

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• 作者：Yu-Juei Hsu^a ; ^b ; Shih-Che Hsu^b ; Chiao-Po Hsu^c ; Yen-Hui Chen^d ; Yung-Lung Chang^b ; Junichi Sadoshima^e ; Shih-Ming Huang^b ; Chien-Sung Tsai^f ; ^g ; Chih-Yuan Lin^g ; ^{linrock@ms26.hinet.net}
• 关键词：Sirtuin 1 ; Contractile dysfunction ; Endoplasmic reticulum stress ; Apoptosis ; Aging
• 刊名：International Journal of Cardiology
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：228
• 期：Complete
• 页码：543-552
• 全文大小：1725 K
• 卷排序：228

文摘

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.MethodsWe evaluated cardiac contractile function, endoplasmic reticulum stress, apoptosis, and oxidative stress in 6- and 12 month-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.ResultsCompared 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 6 months. 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.ConclusionThe 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.