Heart Center, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China.
Oxid Med Cell Longev. 2021 Mar 3;2021:5545261. doi: 10.1155/2021/5545261. eCollection 2021.
Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH.
线粒体功能障碍被认为是心肌肥厚发生和发展的关键因素。线粒体功能障碍的发生和心肌肥厚（CH）发展的机制尚不完全清楚。本研究基于使用多种生物信息学分析，对来自主动脉缩窄（TAC）模型的 scRNA-seq 和微阵列数据集进行组织和分析，以检查线粒体功能障碍在 CH 病理生理学中的潜在作用。结果表明，NADH：泛醌氧化还原酶核心亚基 S1-（Ndufs1-）依赖性线粒体功能障碍在压力超负荷诱导的 CH 中起关键作用。此外，使用 TAC 心肌肥厚小鼠模型的动物研究表明，与正常对照组相比，肥厚心肌组织中 Ndufs1 的表达明显下调。在血管紧张素 II（Ang II）诱导的心肌细胞肥大模型中，Ang II 处理显著下调了心肌细胞中 Ndufs1 的表达。机制研究表明，Ndufs1 敲低诱导 CH；降低线粒体 DNA 含量、线粒体膜电位（MMP）和线粒体质量；并增加心肌细胞中线粒体活性氧（ROS）的产生。另一方面，Ang II 处理上调了心房利钠肽、脑利钠肽和肌球蛋白重链 β 的表达水平；降低了线粒体 DNA 含量、MMP 和线粒体质量；并增加了心肌细胞中线粒体 ROS 的产生。Ndufs1 在大鼠心肌细胞中的过表达显著减弱了 Ang II 的介导作用。总之，我们的结果表明 Ndufs1 在肥厚心肌组织中下调，机制研究结果表明 Ndufs1 缺乏可能导致心肌细胞中线粒体功能障碍，这可能与 CH 的发生和发展有关。
