Department of Clinical Pharmacy, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004 Shaanxi Province, China.
Department of Pharmacy, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, 710054 Shaanxi Province, China.
Oxid Med Cell Longev. 2021 Aug 30;2021:9979706. doi: 10.1155/2021/9979706. eCollection 2021.
Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome , Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.
血管紧张素 II（Ang II）诱导的心肌肥厚和细胞凋亡是心力衰竭早期的主要特征。胆碱具有心脏保护作用；然而，其对 Ang II 诱导的心肌细胞凋亡的影响尚不清楚。在这项研究中，使用心肌细胞凋亡模型（将新生大鼠心肌细胞暴露于 Ang II（10 μM，48 h）诱导凋亡）研究了胆碱调节 Ang II 诱导的心肌细胞凋亡的作用和潜在机制。胆碱促进热休克转录因子 1（HSF1）核易位和 Notch1 细胞内结构域（NICD）的表达。因此，胆碱减弱了 Ang II 诱导的线粒体活性氧（mtROS）增加，并促进促凋亡蛋白从线粒体释放，包括细胞色素 C、Omi/高温需求蛋白 A2 和第二线粒体激活的半胱天冬酶/直接凋亡抑制蛋白结合低 P。这些事件的逆转减弱了 Ang II 诱导的心肌细胞大小增加和末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记阳性细胞的数量，推测这是通过 3 型毒蕈碱乙酰胆碱受体（M3AChR）实现的。事实上，下调 M3AChR 或 Notch1 阻断了胆碱介导的 NICD 和核 HSF1 表达上调，并抑制了线粒体凋亡途径和心肌细胞凋亡，表明 M3AChR 和 Notch1/HSF1 的激活赋予了胆碱的保护作用。在平行研究中，给大鼠输注 Ang II 4 周以诱导心脏凋亡。结果表明，胆碱以与 Notch1/HSF1 通路激活相关的方式缓解 Ang II 输注大鼠的心脏重构和细胞凋亡，与体外研究结果一致。总之，我们的研究结果表明，胆碱通过激活 M3AChR 和 Notch1/HSF1 抗氧化信号来阻止氧化损伤和心肌细胞凋亡，并提示 Notch1/HSF1 信号通路在调节心肌细胞凋亡中发挥新的作用。
