Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 80756, Taiwan.
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80756, Taiwan.
BMC Cardiovasc Disord. 2024 May 30;24(1):287. doi: 10.1186/s12872-024-03953-5.
The activation of G protein-coupled receptors (GPCR) signaling by external stimuli has been implicated in inducing cardiac stress and stress responses. GPR22 is an orphan GPCR expressed in brains and hearts, while its expression level is associated with cardiovascular damage in diabetes. Previous studies have suggested a protective role of GPR22 in mechanical cardiac stress, as loss of its expression increases susceptibility to heart failure post-ventricular pressure overload. However, the involvement and underlying signaling of GPR22 in cardiac stress response to ischemic stress remains unexplored.
In this study, we used cultured cells and a transgenic mouse model with cardiomyocyte-specific GPR22 overexpression to investigate the impact of ischemic stress on GPR22 expression and to elucidate its role in myocardial ischemic injury. Acute myocardial infarction (AMI) was induced by left coronary artery ligation in eight-week-old male GPR22 transgenic mice, followed by histopathological and biochemical examination four weeks post-AMI induction.
GPR22 expression in H9C2 and RL-14 cells, two cardiomyocyte cell lines, was decreased by cobalt chloride (CoCl) treatment. Similarly, reduced expression of myocardial GPR22 was observed in mice with AMI. Histopathological examinations revealed a protective effect of GPR22 overexpression in attenuating myocardial infarction in mice with AMI. Furthermore, myocardial levels of Bcl-2 and activation of PI3K-Akt signaling were downregulated by ischemic stress and upregulated by GPR22 overexpression. Conversely, the expression levels of caspase-3 and phosphorylated ERK1/2 in the infarcted myocardium were downregulated with GPR22 overexpression.
Myocardial ischemic stress downregulates cardiac expression of GPR22, whereas overexpression of GPR22 in cardiomyocytes upregulates Akt signaling, downregulates ERK activation, and mitigates ischemia-induced myocardial injury.
外部刺激激活 G 蛋白偶联受体 (GPCR) 信号转导与诱导心脏应激和应激反应有关。GPR22 是一种在大脑和心脏中表达的孤儿 GPCR，其表达水平与糖尿病中的心血管损伤有关。先前的研究表明，GPR22 在机械性心脏应激中具有保护作用，因为其表达的丧失会增加心力衰竭后心室压力超负荷的易感性。然而，GPR22 在心脏对缺血应激的应激反应中的参与和潜在信号仍未被探索。
在这项研究中，我们使用培养的细胞和一种具有心肌细胞特异性 GPR22 过表达的转基因小鼠模型，研究缺血应激对 GPR22 表达的影响，并阐明其在心肌缺血损伤中的作用。通过左冠状动脉结扎在 8 周龄雄性 GPR22 转基因小鼠中诱导急性心肌梗死 (AMI)，并在 AMI 诱导后 4 周进行组织病理学和生化检查。
两种心肌细胞系 H9C2 和 RL-14 中的 GPR22 表达在钴氯化物 (CoCl) 处理下降低。同样，AMI 小鼠心肌中的 GPR22 表达也减少。组织病理学检查显示，AMI 小鼠中 GPR22 的过表达具有减轻心肌梗死的保护作用。此外，缺血应激下调了心肌中 Bcl-2 的表达和 PI3K-Akt 信号的激活，而上调了 GPR22 的过表达。相反，GPR22 过表达下调了梗死心肌中 caspase-3 和磷酸化 ERK1/2 的表达水平。
心肌缺血应激下调心脏 GPR22 的表达，而心肌细胞中 GPR22 的过表达上调 Akt 信号，下调 ERK 激活，并减轻缺血诱导的心肌损伤。
