Liu Yan, Li Zixuan, Xu Xinhe, Zou Yan, Zhang Miaomiao, Chen Yingyu, Zhu Wenwu, Han Bing
Xuzhou Clinical College of Xuzhou Medical University, Division of Cardiology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China.
Xuzhou Institute of Cardiovascular Disease, Xuzhou, Jiangsu, China.
Front Pharmacol. 2025 Mar 20;16:1529652. doi: 10.3389/fphar.2025.1529652. eCollection 2025.
The incidence of ischemic cardiomyopathy increases annually worldwide, and it is the leading cause of mortality in China. Although interventional diagnostic and therapeutic techniques can promptly open the culprit vessels, myocardial ischemia-reperfusion injury (MIRI), resulting from restored blood flow, is often inevitable. Semaglutide (Sem), a novel GLP-1 analogue, is primarily utilized in managing Type 2 diabetes mellitus (T2DM). Recent research indicates that semaglutide may reduce the risk of major adverse cardiovascular events. Therefore, the purpose of this study is to explore whether semaglutide can ameliorate MIRI and explore its potential mechanism.
: A mouse model of myocardial ischemia-reperfusion (I/R) was created by ligating the left anterior descending coronary artery (LAD) first for 45 min and then reperfusing the heart for 24 h. Assessment of cardiac function and fibrosis were conducted through small animal ultrasound and Masson's staining. It was observed that semaglutide enhanced cardiac function recovery and diminished fibrosis in the I/R model. experiments, semaglutide proved to mitigate oxidative stress and inhibit ferroptosis in cardiomyocytes. RNA sequencing showed that S100 calcium binding protein A9 (S100A9) was the target gene of semaglutide to protect against MIRI. , experiments showed that semaglutide decreased the expression of S100A9 by activating the Protein Kinase C(PKC) pathway, thus inhibiting ferroptosis in cardiomyocytes.
Semaglutide can reduce I/R-induced myocardial injury by inhibiting the ferroptosis of cardiomyocytes. In the mechanism, semaglutide mainly reduce the expression of S100A9 via the activation of PKC signaling pathway. Therefore, semaglutide is considered as a potential treatment option for MIRI.
全球范围内，缺血性心肌病的发病率逐年上升，在中国它是导致死亡的主要原因。尽管介入诊断和治疗技术能够迅速开通罪犯血管，但血流恢复所导致的心肌缺血再灌注损伤（MIRI）往往难以避免。司美格鲁肽（Sem）是一种新型胰高血糖素样肽-1（GLP-1）类似物，主要用于治疗2型糖尿病（T2DM）。近期研究表明，司美格鲁肽可能降低主要不良心血管事件的风险。因此，本研究旨在探讨司美格鲁肽是否能改善MIRI并探究其潜在机制。
通过首先结扎左冠状动脉前降支（LAD）45分钟，然后使心脏再灌注24小时，建立心肌缺血再灌注（I/R）小鼠模型。通过小动物超声和Masson染色对心脏功能和纤维化进行评估。观察到司美格鲁肽可促进I/R模型中心脏功能的恢复并减少纤维化。实验表明，司美格鲁肽可减轻心肌细胞中的氧化应激并抑制铁死亡。RNA测序显示，S100钙结合蛋白A9（S100A9）是司美格鲁肽预防MIRI的靶基因。此外，实验表明司美格鲁肽通过激活蛋白激酶C（PKC）途径降低S100A9的表达，从而抑制心肌细胞中的铁死亡。
司美格鲁肽可通过抑制心肌细胞的铁死亡来减轻I/R诱导的心肌损伤。在机制上，司美格鲁肽主要通过激活PKC信号通路降低S100A9的表达。因此，司美格鲁肽被认为是治疗MIRI的一种潜在选择。
