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

Summary

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 the