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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: GPR22 expression in H9C2 and RL-14 cells, two cardiomyocyte cell lines, was decreased by cobalt chloride (CoCl2) 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: GPR22 expression in H9C2 and RL-14 cells, two cardiomyocyte cell lines, was decreased by cobalt chloride (CoCl2) 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.
CONCLUSIONS: 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.
摘要：
背景：外部刺激对G蛋白偶联受体（GPCR）信号的激活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，而其表达水平与糖尿病患者心血管损害有关。先前的研究表明，GPR22在机械性心脏压力中具有保护作用，由于其表达缺失增加了对心室压力超负荷后心力衰竭的易感性。然而,GPR22在对缺血性应激的心脏应激反应中的参与和潜在信号传导仍未被研究.
方法：在本研究中，我们使用培养细胞和心肌细胞特异性GPR22过表达的转基因小鼠模型来研究缺血应激对GPR22表达的影响,并阐明其在心肌缺血损伤中的作用.在八周龄雄性GPR22转基因小鼠中通过左冠状动脉结扎诱导急性心肌梗死（AMI），AMI诱导后四周进行组织病理学和生化检查。
结果：GPR22在H9C2和RL-14细胞中的表达，两个心肌细胞系，通过氯化钴(CoCl2)处理降低。同样，在AMI小鼠中观察到心肌GPR22的表达降低。组织病理学检查显示，GPR22过表达对减轻AMI小鼠心肌梗塞具有保护作用。此外，心肌Bcl-2水平和PI3K-Akt信号的激活被缺血应激下调,而GPR22过表达上调.相反，GPR22过表达下调梗死心肌中caspase-3和磷酸化ERK1/2的表达水平。
结论：心肌缺血应激下调GPR22的心脏表达，而心肌细胞中GPR22的过表达上调Akt信号，下调ERK激活，减轻缺血引起的心肌损伤。
方法：在本研究中，我们使用培养细胞和心肌细胞特异性GPR22过表达的转基因小鼠模型来研究缺血应激对GPR22表达的影响,并阐明其在心肌缺血损伤中的作用.在八周龄雄性GPR22转基因小鼠中通过左冠状动脉结扎诱导急性心肌梗死（AMI），AMI诱导后四周进行组织病理学和生化检查。
结果：GPR22在H9C2和RL-14细胞中的表达，两个心肌细胞系，通过氯化钴(CoCl2)处理降低。同样，在AMI小鼠中观察到心肌GPR22的表达降低。组织病理学检查显示，GPR22过表达对减轻AMI小鼠心肌梗塞具有保护作用。此外，心肌Bcl-2水平和PI3K-Akt信号的激活被缺血应激下调,而GPR22过表达上调.相反，GPR22过表达下调梗死心肌中caspase-3和磷酸化ERK1/2的表达水平。
结论：心肌缺血应激下调GPR22的心脏表达，而心肌细胞中GPR22的过表达上调Akt信号，下调ERK激活，减轻缺血引起的心肌损伤。
