Endothelial cell HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction
Endothelial cell HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction
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DOI：
10.1172/jci.insight.139640
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发表时间：
2020-09-17
期刊：
影响因子：
8
通讯作者：
Li, Chuanfu
中科院分区：
文献类型：
--
作者：
Fan, Min;Yang, Kun;Li, Chuanfu
血管生成是心肌梗死（MI）后心脏功能恢复所必需的。HSPA12B主要在内皮细胞中表达，是血管生成所必需的。Yes-associated protein （YAP）在肿瘤血管生成中起重要作用。本研究探讨了HSPA12B和YAP在心肌梗死后血管生成中的协同作用。沉默HSPA12B或YAP均可损伤缺氧，促进内皮细胞增殖和血管生成。缺氧后HSPA12B缺乏抑制YAP表达和核易位。YAP的下调可减弱缺氧刺激的HSPA12B核易位，并消除hspa128促进的内皮细胞血管生成。在机制上，缺氧诱导内皮细胞HSPA12B和YAP之间的相互作用。ChIP实验表明，HSPA12B是YAP/转录增强相关结构域4 （TEAD4）的靶基因，也是YAP相关血管生成的共激活因子。使用MI模型的体内研究表明，与WT小鼠相比，内皮细胞特异性缺乏HSPA12B （eHspal2b(-/-)）或YAP （eYop(-/-)）会损害血管生成并加重心功能障碍。心肌梗死增加了WT心脏中YAP的表达和核易位，但对el-ispol2b（-/-）心脏没有影响。HSPA12B表达和核易位在WT型心肌梗死中上调，而在eYap（-/-）型心肌梗死中上调。我们的数据表明内皮HSPA12B是YAP/TEAD4的靶点和共激活因子，并与YAP协同调节心肌梗死后内皮血管生成。
Angiogenesis is essential for cardiac functional recovery after myocardial infarction (MI). HSPA12B is predominately expressed in endothelial cells and required for angiogenesis. Yes-associated protein (YAP) plays an important role in tumor angiogenesis. This study investigated the cooperative role of HSPA12B and YAP in angiogenesis after MI. Silencing of either HSPA12B or YAP impaired hypoxia-promoted endothelial cell proliferation and angiogenesis. Deficiency of HSPA12B suppressed YAP expression and nuclear translocation after hypoxia. Knockdown of YAP attenuated hypoxia-stimulated HSPA12B nuclear translocation and abrogated HSPA128-promoted endothelial cell angiogenesis. Mechanistically, hypoxia induced an interaction between endothelial HSPA12B and YAP. ChIP assay showed that HSPA12B is a target gene of YAP/transcriptional enhanced associated domain 4 (TEAD4) and a coactivator in YAP-associated angiogenesis. In vivo studies using the MI model showed that endothelial cell-specific deficiency of HSPA12B (eHspal2b(-/-)) or YAP (eYop(-/-)) impaired angiogenesis and exacerbated cardiac dysfunction compared with WT mice. MI increased YAP expression and nuclear translocation in WT hearts but not el-ispol2b(-/-) hearts. HSPA12B expression and nuclear translocation were upregulated in WT MI hearts but not eYap(-/- )MI myocardium. Our data demonstrate that endothelial HSPA12B is a target and coactivator for YAP/TEAD4 and cooperates with YAP to regulate endothelial angiogenesis after MI.