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

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

EP4 receptor; TGF‐β signaling; cardiac fibroblast; cardiac fibrosis; cardiomyocyte; isoproterenol.