SERCA2的5-羟色胺化在低氧性肺动脉高压肺静脉重塑中的作用及其机制

除肺动脉外，肺静脉重塑也是低氧性肺动脉高压（HPAH）突出的病理表现。肌内质网钙三磷酸腺苷酶2（SERCA2）翻译后修饰所致的活性抑制可激活瞬间受体电位阳离子（TRPC）通道，促发外钙内流；而5-羟色胺（5-HT）化是新的翻译后修饰方式。我们前期发现TRPC6在肺静脉重塑中起重要作用；低氧上调SERCA2的5-HT化水平。我们采用大鼠肺静脉平滑肌细胞（PVSMC），建立5-HT化调控蛋白TG2以及TRPC6沉默和过表达模型，研究5-HT化对SERCA2活性的影响，并探讨SERCA2活性改变对细胞生物学行为的影响及机制；建立TG2敲除小鼠的HPAH模型，研究SERCA2的5-HT化在肺静脉重塑中的作用。从而在分子、细胞、组织和整体水平上论证“SERCA2的5-HT化抑制其活性，激活TRPC6介导的外钙内流，促进PVSMC增殖和迁移，导致HPAH肺静脉重塑”的假说，为HPAH的防治提供新思路。

Pulmonary vein remodeling is the principal pathological manifestation of hypoxic pulmonary arterial hypertension (HPAH) besides pulmonary artery remodeling. After post-translational modification of sarco endoplasmic reticulum calcium adenosine triphosphatase 2 (SERCA2) induced by inhibiting activation, it triggers calcium influx via transient receptor potential cation (TRPC) channels, and serotonylation is a new post-translational modification. We previously found that TRPC6 plays an important role in pulmonary vein remodeling and hypoxia increases the serotonylation of SERCA2. We will establish TG2 (the key regulatory protein of serotonylation), TRPC6 silencing, and an over-expression model of rat pulmonary vein smooth muscle cell (PVSMC). Then, we will study the effect of serotonylation on SERCA2 activity, and the effect of changes in SERCA2 activity and the mechanism on biological behaviors of PVSMC. Next, we plan to investigate the influence of SERCA2 serotonylation on pulmonary vein remodeling via TG2 knockout mouse models of HPAH. Our study will demonstrate the hypothesis that hypoxia activates calcium influx mediated by TRPC6 channel via SERCA2 serotonylation, promotes the proliferation and migration of PVSMC, and leads to pulmonary vein remodeling from aspects of molecular, cell, tissue, and animal models, so as to provide new insights for the prevention and treatment of HPAH.