Peng Shi, Lu Xiao-Feng, Qi Yi-Ding, Li Jing, Xu Juan, Yuan Tian-You, Wu Xiao-Yu, Ding Yu, Li Wen-Hua, Zhou Gen-Qing, Wei Yong, Li Jun, Chen Song-Wen, Liu Shao-Wen
Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, China.
Oxid Med Cell Longev. 2020 Sep 17;2020:9815039. doi: 10.1155/2020/9815039. eCollection 2020.
We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway.
, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. , we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression.
Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway.
LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.
我们旨在研究LCZ696是否通过调节Sirt3/MnSOD途径来预防病理性心脏肥大。
我们建立了一个主动脉缩窄动物模型以诱发压力超负荷诱导的心力衰竭。随后，通过灌胃法给小鼠服用LCZ696，持续4周。之后，在处死小鼠前对其进行经胸超声心动图检查。此外，我们用去甲肾上腺素刺激原代新生大鼠心肌细胞，并使用小干扰RNA敲低Sirt3表达。
病理性肥大刺激导致心脏肥大和纤维化，并降低了Sirt3和MnSOD的表达水平。LCZ696减轻了氧化活性氧（ROS）的积累和心肌细胞凋亡。此外，Sirt3缺乏消除了LCZ696对心肌细胞肥大的保护作用，表明LCZ696通过Sirt3依赖性途径诱导MnSOD上调和AMPK磷酸化。
LCZ696可能通过调节Sirt3/MnSOD途径减轻压力超负荷诱导的心力衰竭中的心肌氧化应激和凋亡。
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