Shen Jing, Miao Junqiu, Wu Lifei, Wang Deping, Li Guang, Wang Haixiong, Cao Jimin
Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan, 030001, China.
Key Laboratory of Medical Electrophysiology at Southwest Medical University, Ministry of Education, and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646099, China.
Hum Cell. 2025 Apr 25;38(3):96. doi: 10.1007/s13577-025-01220-z.
Cardiac hypertrophy is a major risk factor for heart failure and sudden cardiac death, but its molecular mechanisms have not been well clarified. Synaptotagmin-1 (SYT1) is an important regulator of exocytosis and apoptosis and has been found expressed in the myocardium, while its functions in heart diseases have rarely been studied. Here, we investigated the role and mechanism of SYT1 in pressure overload-induced cardiac hypertrophy. Transverse aortic constriction (TAC) surgeries were performed to induce cardiac hypertrophy in global Syt1 knockout (Syt1) mice and C57BL/6J wild-type (WT) littermates in vivo, with respective sham mice as negative controls. Cardiomyocyte hypertrophy was induced by angiotensin II (Ang II) in H9C2 cells in vitro. The results showed that SYT1 expression was significantly upregulated in WT-TAC mice and in Ang II-treated H9C2 cells. Blocking angiotensin receptor by losartan decreased SYT1 expression in Ang II-treated H9C2 cells. Syt1 mice showed significantly exacerbated cardiac hypertrophy, dysfunction, fibrosis, apoptosis and phosphorylation of myocardial p38 MAPK in response to TAC compared to WT mice. Knocking down SYT1 using siRNA in H9C2 cells aggravated Ang II-induced cell hypertrophy and apoptosis, and also enhanced p38 MAPK phosphorylation. Inhibition of p38 MAPK by SB203580 significantly alleviated the hypertrophy and apoptosis in Ang II-treated H9C2 cells. We conclude that deficiency of SYT1 aggravates pressure overload-induced cardiac hypertrophy via the p38 MAPK signaling pathway. The study elucidates a novel role of SYT1 in cardiac remodeling.
心肌肥厚是心力衰竭和心源性猝死的主要危险因素，但其分子机制尚未完全阐明。突触结合蛋白-1（SYT1）是胞吐作用和细胞凋亡的重要调节因子，已发现其在心肌中表达，而其在心脏病中的功能鲜有研究。在此，我们研究了SYT1在压力超负荷诱导的心肌肥厚中的作用及机制。在体内对全球Syt1基因敲除（Syt1）小鼠和C57BL/6J野生型（WT）同窝小鼠进行横向主动脉缩窄（TAC）手术以诱导心肌肥厚，分别以假手术小鼠作为阴性对照。在体外，用血管紧张素II（Ang II）诱导H9C2细胞发生心肌细胞肥大。结果显示，WT-TAC小鼠和Ang II处理的H9C2细胞中SYT1表达显著上调。用氯沙坦阻断血管紧张素受体可降低Ang II处理的H9C2细胞中SYT1的表达。与WT小鼠相比，Syt1小鼠在TAC后表现出明显加重的心肌肥厚、功能障碍、纤维化、细胞凋亡以及心肌p38 MAPK磷酸化。在H9C2细胞中用小干扰RNA（siRNA）敲低SYT1会加重Ang II诱导的细胞肥大和凋亡，同时也增强p38 MAPK磷酸化。用SB203580抑制p38 MAPK可显著减轻Ang II处理的H9C2细胞中的肥大和凋亡。我们得出结论，SYT1缺乏通过p38 MAPK信号通路加重压力超负荷诱导的心肌肥厚。该研究阐明了SYT1在心脏重塑中的新作用。
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