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

Abstract Sustained β‐adrenergic activation induces cardiac fibrosis characterized by excessive deposition of extracellular matrix (ECM). Prostaglandin E 2 (PGE 2 ) 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.