YAP在血管紧张素II导致的高血压血管重塑中的作用和机制研究

Hypertensive vascular remodeling is characterized as extracellular matrix remodeling and collagen over-deposition, resulting in serious damage of target organs such as heart, brain and kidney. It is the result of abnormal expression of cytokines related with hypertensive vascular remodeling which regulated by transcription factors such as Smad3. YAP is a new co-activator of transcription factors which regulates the myocyte size in the heart and the vascular smooth muscle cell phenotypic switch. Our studies showed that the expression of YAP is increased in hypertensive vascular remodeling. In previous work, we have demonstrated that as a key transcription factors in hypertensive vascular remodeling induced by Angiotensin II, Smad3 was regulated by PARP1. These results suggest that YAP may be as a mediated-protein participates in hypertensive vascular remodeling relying on the influence of the transcription factors regulating by PARP1. The results will provide us with new therapeutic targets for hypertensive vascular remodeling.

高血压血管重塑是指细胞外基质重塑和胶原过度沉积，它是导致心脏、脑、肾脏等靶器官纤维化和功能受损的重要原因。大量细胞因子的表达异常直接参与了高血压血管重塑，而其合成和分泌是由相关转录因子（如Smad3等）调控的。YAP是一种新发现的共合作转录因子，在心脏肥大和血管平滑肌的表型转化中具有重要作用，我们的研究发现高血压血管重塑中YAP表达增加。Smad3是高血压中AngII诱导血管重塑的最关键转录因子，前期工作已经证实其转录活性受PARP1调控。由此推测，YAP可能作为"中介蛋白"通过影响PARP1调控相关转录因子活性参与高血压血管重塑。本课题拟通过建立Ang II诱导的高血压小鼠模型及细胞模型探索YAP在高血压血管重塑中的作用；并通过研究YAP对 PARP1介导的相关转录因子活性的影响阐明作用机制；为高血压血管重塑提供新的理论和实验依据，也为高血压血管重塑的治疗提供新的靶点。

高血压血管重塑是指细胞外基质重塑和胶原过度沉积,它是导致心脏、脑、肾脏等靶器官纤维化和功能受损的重要原因。大量细胞因子的表达异常直接参与了高血压血管重塑,而其合成和分泌是由相关转录因子(如Smad3等)调控的。YAP是一种新发现的共合作转录因子,在心脏肥大和血管平滑肌的表型转化中具有重要作用,我们的研究发现高血压血管重塑中YAP表达增加。Smad3是高血压中AngII诱导血管重塑的最关键转录因子,前期工作已经证实其转录活性受PARP1调控。由此推测,YAP可能作为"中介蛋白"通过影响PARP1调控相关转录因子活性参与高血压血管重塑。我们的研究发现非磷酸化的YAP进入细胞核，继而在细胞核内与转录因子Chrebp直接结合，进而上调其靶基因ACC、LPK的表达，为脂质代谢及糖代谢的调控提供了新的机制；另外，Yap能够和线粒体转录因子TFAM结合，部分通过TFAM增加线粒体的复制和合成，增加线粒体复合体的活性，为线粒体的合成机制提供了新的思路；我们课题组还证实了抑制PARP可以减轻慢性酒精肝的损伤，为酒精肝的治疗提供了新的方向。