Critical role of PAFR/YAP1 positive feedback loop in cardiac fibrosis

Aberrant activation of cardiac fibroblasts is the main cause and character of cardiac fibrosis, and inhibition of cardiac fibrosis becomes a promising treatment for cardiac diseases. Platelet-activating factor (PAF) and Hippo pathway is recently recognized as key signaling mechanisms in cardiovascular diseases. In this study we explored the potential roles of PAF and Hippo signaling pathway in cardiac fibrosis. Myocardial infarction (MI) was induced in mice by left anterior descending artery ligation. After 28 days, the mice were sacrificed, and the hearts were collected for analyses. We showed that PAF receptor (PAFR) and yes-associated protein 1 (YAP1, a key effector in the Hippo pathway) were significantly increased in the heart of MI mice. Increased expression of PAFR and YAP1 was also observed in angiotensin II (Ang II)-treated mouse cardiac fibroblasts. In mouse cardiac fibroblasts, forced expression of YAP1 increased cell viability, resulted in collagen deposition and promoted fibroblast-myofibroblast transition. We showed that PAF induced fibrogenesis through activation of YAP1 and promoted its nuclear translocation via interacting with PAFR, while YAP1 promoted the expression of PAFR by binding to and activating transcription factor TEAD1. More importantly, silencing PAFR or YAP1 by shRNA, or using transgenic mice to induce the conditional deletion of YAP1 in cardiac fibroblasts, impeded cardiac fibrosis and improved cardiac function in MI mice. Taken together, this study elucidates the role and mechanisms of PAFR/YAP1 positive feedback loop in cardiac fibrosis, suggesting a potential role of this pathway as novel therapeutic targets in cardiac fibrosis.