Deleterious effects of cardiomyocyte-specific prostaglandin E2 EP3 receptor overexpression on cardiac function after myocardial infarction.
Deleterious effects of cardiomyocyte-specific prostaglandin E2 EP3 receptor overexpression on cardiac function after myocardial infarction.
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DOI：
10.1016/j.lfs.2022.121277
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发表时间：
2022-12
期刊：
影响因子：
6.1
通讯作者：
DruAnne L Maxwell;T. Bryson;D. Taube;Jiang Xu;E. Peterson;P. Harding
中科院分区：
文献类型：
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作者：
DruAnne L Maxwell;T. Bryson;D. Taube;Jiang Xu;E. Peterson;P. Harding
目的前列腺素 E2 (PGE2) 是一种脂质激素，通过 4 种不同的 G 蛋白偶联受体亚型发出信号，从而调节关键的生理过程。我们的实验室之前曾报道，PGE2 通过其 EP3 受体降低离体心肌细胞水平和离体工作心脏制剂中的心肌收缩力。因此，我们假设心肌细胞特异性过度表达 PGE2 EP3 受体进一步降低心肌梗塞引起的心力衰竭小鼠模型的心脏功能。 主要方法我们的研究使用 EP3 转基因小鼠 (EP3 TG) 测试了这一假设，该小鼠在心肌细胞中过度表达人 EP3 的猪类似物及其野生型 (WT) 同窝小鼠。在心肌梗死 (MI) 或假手术后 2 周，通过超声心动图、RT-PCR、免疫组织化学和组织学对小鼠进行分析。 主要发现我们发现，与 WT 假手术对照组相比，EP3 TG 假手术对照组的射血分数降低、缩短分数降低、收缩期和舒张期左心室尺寸增加。此外，心肌梗塞后EP3 TG小鼠的血脂进一步减少。此外，对从 EP3 TG 小鼠分离的心肌细胞进行的单细胞分析显示，在基础条件下收缩力降低。 EP3的过度表达显着增加了假手术组的心脏肥大、间质胶原分数、巨噬细胞和T细胞浸润。有趣的是，心肌梗死后，肥厚没有变化，但胶原蛋白分数和炎症细胞浸润发生变化。 意义 EP3 过度表达会降低基础条件下的心功能，心肌梗死后这种情况会加剧。
AimsProstaglandin E2 (PGE2) is a lipid hormone that signals through 4 different G-protein coupled receptor subtypes which act to regulate key physiological processes. Our laboratory has previously reported that PGE2 through its EP3 receptor reduces cardiac contractility at the level of isolated cardiomyocytes and in the isolated working heart preparation. We therefore hypothesized that cardiomyocyte specific overexpression of the PGE2 EP3 receptor further decreases cardiac function in a mouse model of heart failure produced by myocardial infarction.Main methodsOur study tested this hypothesis using EP3 transgenic mice (EP3 TG), which overexpress the porcine analogue of human EP3 in the cardiomyocytes, and their wildtype (WT) littermates. Mice were analyzed 2 wks after myocardial infarction (MI) or sham operation by echocardiography, RT-PCR, immunohistochemistry, and histology.Key findingsWe found that the EP3 TG sham controls had a reduced ejection fraction, reduced fractional shortening, and an increased left ventricular dimension at systole and diastole compared to the WT sham controls. Moreover, there was a further reduction in the EP3 TG mice after myocardial infarction. Additionally, single-cell analysis of cardiomyocytes isolated from EP3 TG mice showed reduced contractility under basal conditions. Overexpression of EP3 significantly increased cardiac hypertrophy, interstitial collagen fraction, macrophage, and T-cell infiltration in the sham operated group. Interestingly, after MI, there were no changes in hypertrophy but there were changes in collagen fraction, and inflammatory cell infiltration.SignificanceOverexpression of EP3 reduces cardiac function under basal conditions and this is exacerbated after myocardial infarction.