Zhu Qiuxia, Luo Yong, Wen Yuetao, Wang Ding, Li Jing, Fan Zhongcai
Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Number 25, Taiping Street. Jiangyang District, 400042, Luzhou, Sichuan, China.
Department of Cardiology, Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, Number 725, Jiangzhou Avenue, Jiangjin District, 402260, Chongqing, China.
Biochem Biophys Res Commun. 2023 Mar 5;647:1-8. doi: 10.1016/j.bbrc.2023.01.049. Epub 2023 Jan 17.
Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.
细胞凋亡是心肌缺血/再灌注（I/R）损伤后的主要病理生理变化。胰高血糖素样肽1（GLP-1）及其受体GLP-1R在心血管系统中广泛表达，且GLP-1/GLP-1R激活蛋白激酶G（PKG）相关信号通路。因此，本研究检测了新型GLP-1类似物司美格鲁肽是否通过激活PKG/PKCε/ERK1/2通路来抑制I/R损伤诱导的心肌细胞凋亡。我们诱导大鼠发生心肌I/R损伤以及H9C2细胞发生缺氧/复氧（H/R）损伤，并检测司美格鲁肽、一种PKG类似物（8-溴-cGMP）和一种PKG抑制剂（KT-5823）对PKG/PKCε/ERK1/2通路及心肌细胞凋亡的影响。我们发现司美格鲁肽上调GLP-1R水平，且司美格鲁肽和8-溴-cGMP均激活PKG/PKCε/ERK1/2通路，抑制心肌梗死（MI），降低hs-cTNT水平，升高NT-proBNP水平，并抑制I/R大鼠和H/R H9C2细胞中的心肌细胞凋亡。然而，KT-5823产生了与司美格鲁肽和8-溴-cGMP相反的作用，且KT-5823减弱了司美格鲁肽的心脏保护作用。总之，司美格鲁肽通过激活PKG/PKCε/ERK1/2通路抑制I/R损伤诱导的心肌细胞凋亡。GLP-1/GLP-1R参与激活PKG/PKCε/ERK1/2通路的有益作用可能为心肌I/R损伤提供一种新的治疗方法。
