Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
Zhuhai People's Hospital, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China.
Acta Pharmacol Sin. 2022 Nov;43(11):2862-2872. doi: 10.1038/s41401-022-00903-9. Epub 2022 Apr 8.
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.
心肌成纤维细胞的异常激活是心肌纤维化的主要原因和特征，抑制心肌纤维化成为心脏疾病有希望的治疗方法。血小板激活因子 (PAF) 和 Hippo 通路最近被认为是心血管疾病的关键信号机制。在这项研究中，我们探讨了 PAF 和 Hippo 信号通路在心肌纤维化中的潜在作用。通过结扎左前降支诱导小鼠心肌梗死。28 天后，处死小鼠，收集心脏进行分析。我们表明，PAF 受体 (PAFR) 和 yes 相关蛋白 1 (YAP1，Hippo 通路中的关键效应物) 在 MI 小鼠的心脏中显著增加。在血管紧张素 II (Ang II) 处理的小鼠心肌成纤维细胞中也观察到 PAFR 和 YAP1 的表达增加。在小鼠心肌成纤维细胞中，YAP1 的强制表达增加了细胞活力，导致胶原蛋白沉积并促进成纤维细胞-肌成纤维细胞转化。我们表明，PAF 通过激活 YAP1 诱导纤维发生，并通过与 PAFR 相互作用促进其核易位，而 YAP1 通过结合并激活转录因子 TEAD1 促进 PAFR 的表达。更重要的是，通过 shRNA 沉默 PAFR 或 YAP1，或使用转基因小鼠在心肌成纤维细胞中诱导 YAP1 的条件性缺失，可阻止 MI 小鼠的心肌纤维化并改善心脏功能。总之，这项研究阐明了 PAFR/YAP1 正反馈环在心肌纤维化中的作用和机制，表明该途径作为心肌纤维化的新型治疗靶点具有潜在作用。
