Targeting the E Prostanoid Receptor EP4 Mitigates Cardiac Fibrosis Induced by β‐Adrenergic Activation

• DOI: 10.1002/advs.202413324
• Publication Date: 2025-02-11T02:51:02Z
• Authors: Hu Xu; Xiuhui Mao; Yali Wang; Chunhua Zhu; Bo Liang; Yihang Zhao; Mengfei Zhou; Lan Ye; Mengting Hong; Huishu Shao; Yashuo Wang; Haonan Li; Yinghui Qi; Yongliang Yang; Lihong Chen; Youfei Guan; Xiaoyan Zhang
• Keywords: Cardiac Fibrosis; Knockout mouse; Prostaglandin E2 receptor; Myocardial fibrosis; Prostanoid

Sustained β-adrenergic activation induces cardiac fibrosis characterized by excessive deposition of extracellular matrix (ECM). Prostaglandin E2 (PGE2) receptor EP4 is essential for cardiovascular homeostasis. This study aims to investigate the roles cardiomyocyte (CM) and fibroblast (CF) in isoproterenol (ISO)-induced fibrosis. By crossing EP4f/f mice with α-MyHC-Cre or S100A4-Cre mice, this work obtains CM-EP4 knockout (EP4f/f-α-MyHCCre+) CF-EP4 (EP4f/f-S100A4Cre+) mice. The both genders are subcutaneously injected ISO (5 mg kg-1 day-1) 7 days. Compared control EP4f/f-α-MyHCCre+ EP4f/f-S100A4Cre+ show a significant improvement diastolic function as assessed echocardiography histological staining, respectively. In CMs, inhibition suppresses ISO-induced TGF-β1 expression via blocking cAMP/PKA pathway. CFs, reversed TGF-β1-triggers production ECM preventing formation TGF-β1/TGF-β complex blocks CF proliferation suppressing ERK1/2 Furthermore, double CM- administration antagonist, grapiprant, markedly improves dysfunction Collectively, demonstrates that contribute activation-induced Targeting may offer novel therapeutic approach