心力衰竭
串扰
刺激
医学
内科学
纤维化
肌肉肥大
炎症
心肌细胞
转化生长因子
调解人
前列腺素E2
内分泌学
信号转导
细胞生物学
生物
物理
光学
作者
Jing-Li Fu,Li Li,Long Chen,Congping Su,Xiu-Ling Feng,Kai Huang,Laxi Zhang,Xiaoyan Yang,Qin Fu
标识
DOI:10.1016/j.yjmcc.2022.07.012
摘要
Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation.
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