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
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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DOI：
10.1016/j.ijcard.2016.11.247
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Lin, Chih-Yuan
中科院分区：
文献类型：
--
作者：
Hsu, Yu-Juei;Hsu, Shih-Che;Lin, Chih-Yuan
背景资料：长寿调节因子Sirtuin 1是一种NAD（+）依赖性组蛋白去乙酰化酶，在衰老诱导的心脏收缩功能障碍期间调节内质网应激并影响心肌细胞凋亡。Sirtuin 1功能在心脏收缩功能障碍相关的老龄化的机制尚未完全阐明。方法：我们评估了心脏收缩功能，内质网应激，细胞凋亡和氧化应激在6个月和12个月大的心脏特异性Sirtuin 1基因敲除（Sirt 1（-/-））和对照（Sirt 1（f/f））小鼠使用蛋白质印迹和免疫组织化学。给小鼠注射蛋白质二硫化物异构酶抑制剂。对于体外分析，将培养的H9 c2心肌细胞暴露于Sirtuin 1抑制剂或激活剂，有或没有线粒体抑制剂，以评估Sirtuin 1对内质网应激、一氧化氮合酶表达和细胞凋亡的影响。蛋白质二硫键异构酶抑制对氧化应激和ER应激相关的细胞凋亡的影响也investigated.Results：与6个月大的Sirt 1（f/f）小鼠相比，12个月大的Sirt 1（-/-）小鼠的收缩力明显受损。这些发现与心肌中内质网应激和细胞凋亡增加一致。在6个月时，Sirt 1（-/-）小鼠的氧化应激和一氧化氮合酶表达的测量值显著高于Sirt 1（f/f）小鼠。在体外实验中发现增加内质网应激介导的细胞凋亡的H9 c2心肌细胞与Sirtuin 1抑制剂处理，Sirtuin 1激活剂的效果得到改善。此外，与体外研究结果一致，在注射蛋白质二硫化物异构酶抑制剂的Sirt 1（-/-）小鼠中证明了心肌收缩力受损。目前的研究表明，衰老心脏的特征是收缩功能障碍，与氧化应激和内质网应激增加有关，Sirtuin 1可能具有保护衰老心脏免受内质网应激抑制的能力。网织介导的凋亡。(C)2016爱思唯尔爱尔兰有限公司版权所有。
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 12 month-old cardiac-specific Sirtuin 1 knockout (Sirt1(-/-)) and control (Sirt1(f/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 Sirt1(f/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 Sirt1(f/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.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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.