Sirtuin 1 aggravates hypertrophic heart failure caused by pressure overload via shifting energy metabolism.
Sirtuin 1 aggravates hypertrophic heart failure caused by pressure overload via shifting energy metabolism.
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DOI：
10.1016/j.bbrc.2022.11.014
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发表时间：
2022-11
影响因子：
3.1
通讯作者：
Tran Ngoc Van Le;L. Zoungrana;Hao Wang;M. Fatmi;Di Ren;Meredith Krause-Hauch;Ji Li
中科院分区：
文献类型：
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作者：
Tran Ngoc Van Le;L. Zoungrana;Hao Wang;M. Fatmi;Di Ren;Meredith Krause-Hauch;Ji Li
Sirtuin1 (SIRT1) 参与调节心血管系统的底物代谢。代谢稳态在肥厚性心力衰竭中起着至关重要的作用。我们假设心脏 SIRT1 可以在压力超负荷引起的心力衰竭期间调节底物代谢。对诱导型心肌细胞 Sirt1 敲除 (icSirt1−/−) 及其野生型同窝小鼠 (Sirt1f/f) C57BL/6J 小鼠进行横主动脉缩窄 (TAC) 手术以诱导压力超负荷。压力过载会导致 Sirt1f/f 小鼠心脏 SIRT1 的上调，但不会导致 icSirt1−/− 小鼠的心脏 SIRT1 上调。 TAC 诱导的压力超负荷引起的心脏收缩功能障碍发生在 Sirt1f/f 小鼠中，但没有发生在 icSirt1−/− 小鼠中。有趣的是，Sirt1f/fheart 在 TAC 手术后表现出收缩性收缩力和电信号急剧减少，而 icSirt1−/−heart 则表现出对 TAC 引起的压力超载引起的病理应激的显着抵抗力，收缩期收缩功能和电特性没有显着变化就证明了这一点。靶向蛋白质组学表明，压力超负荷触发了 SIRT1 相关 IDH2（异柠檬酸脱氢酶 2）的下调，导致线粒体氧化应激增加。此外，在 Sirt1f/f 中观察到代谢变化，但在 icSirt1−/− 心脏中未观察到响应 TAC 诱导的压力超负荷的代谢变化。因此，SIRT1 在压力超负荷期间通过线粒体 IDH2 干扰代谢稳态。抑制 SIRT1 活性有利于压力超负荷相关病理条件下的心脏功能。
Sirtuin1 (SIRT1) is involved in regulating substrate metabolism in the cardiovascular system. Metabolic homeostasis plays a critical role in hypertrophic heart failure. We hypothesize that cardiac SIRT1 can modulate substrate metabolism during pressure overload-induced heart failure. The inducible cardiomyocyte Sirt1 knockout (icSirt1−/−) and its wild type littermates (Sirt1f/f) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery to induce pressure overload. The pressure overload induces upregulation of cardiac SIRT1 in Sirt1f/fbut not icSirt1−/−mice. The cardiac contractile dysfunctions caused by TAC-induced pressure overload occurred in Sirt1f/fbut not in icSirt1−/−mice. Intriguingly, Sirt1f/fheart showed a drastic reduction in systolic contractility and electric signals during post-TAC surgery, whereas icSirt1−/−heart demonstrated significant resistance to pathological stress by TAC-induced pressure overload as evidenced by no significant changes in systolic contractile functions and electric properties. The targeted proteomics showed that the pressure overload triggered downregulation of the SIRT1-associated IDH2 (isocitrate dehydrogenase 2) that resulted in increased oxidative stress in mitochondria. Moreover, metabolic alterations were observed in Sirt1f/fbut not in icSirt1−/−heart in response to TAC-induced pressure overload. Thus, SIRT1 interferes with metabolic homeostasis through mitochondrial IDH2 during pressure overload. Inhibition of SIRT1 activity benefits cardiac functions under pressure overload-related pathological conditions.