Critical role of PAFR/YAP1 positive feedback loop in cardiac fibrosis
Critical role of PAFR/YAP1 positive feedback loop in cardiac fibrosis
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PAFR/YAP1正反馈环在心脏纤维化中的关键作用
DOI：
10.1038/s41401-022-00903-9
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发表时间：
2022-04
影响因子：
8.2
通讯作者：
Hai-hai Liang
中科院分区：
文献类型：
--
作者：
Tian-yu Li;Wei Su;Liang-liang Li;Xiao-guang Zhao;Na Yang;Jia-xin Gai;Xin Lv;Jing Zhang;Meng-qin Huang;Qing Zhang;Wei-hang Ji;Xiao-ying Song;Yu-hong Zhou;Xue-lian Li;Hong-li Shan;Hai-hai Liang
心脏成纤维细胞的异常活化是心脏纤维化的主要原因和特征，抑制心脏纤维化成为治疗心脏疾病的一种有希望的方法。血小板活化因子（PAF）和Hippo信号通路是近年来发现的心血管疾病的重要信号通路。本研究探讨PAF和Hippo信号通路在心肌纤维化中的作用。结扎小鼠左前降支建立心肌梗死模型。28天后，处死小鼠，收集心脏进行分析。我们发现PAF受体（PAFR）和yes相关蛋白1（YAP 1，Hippo通路中的关键效应子）在MI小鼠心脏中显著增加。在血管紧张素II（Ang II）处理的小鼠心脏成纤维细胞中也观察到PAFR和YAP 1表达增加。在小鼠心脏成纤维细胞中，YAP 1的强制表达增加了细胞活力，导致胶原沉积，并促进成纤维细胞-肌成纤维细胞转化。我们发现PAF通过激活YAP 1诱导纤维化，并通过与PAFR相互作用促进其核转位，而YAP 1通过结合并激活转录因子TEAD 1促进PAFR的表达。更重要的是，通过shRNA沉默PAFR或YAP 1，或使用转基因小鼠诱导心脏成纤维细胞中YAP 1的条件性缺失，可以阻止心肌纤维化并改善MI小鼠的心脏功能。综上所述，本研究阐明了PAFR/YAP 1正反馈回路在心脏纤维化中的作用和机制，表明该途径作为心脏纤维化的新治疗靶点的潜在作用。
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.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
Hippo 通路在器官大小控制、组织稳态和癌症中的作用
影响因子：
64.5
作者：
Yu FX;Zhao B;Guan KL
通讯作者：
Guan KL
影响因子：
14.5
作者：
Li, Fu-Long;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang
影响因子：
64.5
作者：
Yu FX;Zhao B;Panupinthu N;Jewell JL;Lian I;Wang LH;Zhao J;Yuan H;Tumaneng K;Li H;Fu XD;Mills GB;Guan KL
通讯作者：
Guan KL
影响因子：
20.1
作者：
Lin Z;von Gise A;Zhou P;Gu F;Ma Q;Jiang J;Yau AL;Buck JN;Gouin KA;van Gorp PR;Zhou B;Chen J;Seidman JG;Wang DZ;Pu WT
通讯作者：
Pu WT