二十二碳六烯酸调控NFATc1抑制肺血管结构重塑的机制

One of the hallmarks of pulmonary arterial hypertension is vascular remodeling. Remodeling of pulmonary blood vessels is characterized to phenotype switching of pulmonary arterial smooth muscle cell(PASMC).Studies have shown nuclear factor of activated T lymphocyte(NFAT) is the main regulator in cellular process of phenotype switching. Our previous results have shown that the level of NFATc1 was up-regulated in the arterial tissue of hypoxic pulmonary hypertension (HPH) rat models.Whereas, docosahexaenoic acid (DHA) attenuated expression of hypoxia-induced NFATc1. Meanwhile, DHA had protective effects on HPH by improving pulmonary vascular remolding in vivo and inhibiting hypoxia-induced proliferation, migration and phenotypic switching of PASMC in vitro. That is to say DHA may prevent pulmonary hypertension ,vascular remodeling in chronic hypoxia model by down regulation the expression of NFATc1. We intend to carry out research on the basis of the preliminary work to explore the role of NFATc1 in protective effects of DHA on HPH. Using HPH rat models and PASMC to establish NFATc1 may be the downstream molecule regulated by DHA in vitro and in vivo. Meanwhile, constructing recombinant adenovirus vectors for NFATc1 gene overexpression and gene silence to discover whether protective effects of DHA on HPH will disappear. We will illustrate that DHA may protect HPH through targeting NFATc1.

肺血管结构重塑是肺动脉高压（PAH）发生的重要病理机制，其中肺动脉平滑肌细胞（PASMC）表型转换是PAH形成的关键环节。研究显示：活化T细胞核因子（NFAT）发挥PASMC表型调控的“分子开关”作用。我们前期发现：在大鼠低氧性肺动脉高压(HPH)形成过程中，肺血管NFATc1表达显著升高，而二十二碳六烯酸（DHA）能抑制低氧诱导的NFATc1的高表达；并且DHA能通过抑制低氧诱导的PASMC的增殖，迁移,维持PASMC收缩表型而降低肺动脉高压。提示：DHA通过调控NFATc1的表达而抑制肺血管重构。本研究拟在前期研究基础上探讨NFATc1在DHA调控肺血管重塑中的作用。分别以HPH和PASMC为模型，从动物和细胞水平研究DHA通过NFATc1调控肺血管重构；并分别过表达和沉默表达NFATc1验证是否逆转DHA的干预作用，以期阐明DHA通过调控NFATc1表达影响肺动脉高压的发生。

肺高压(PH)是肺血管阻力持续升高，右心室负荷不断增加，进而导致进行性右心衰竭甚至死亡的常见严重并发症。肺动脉平滑肌细胞（PASMC）表型转换，过度增殖及凋亡耐受是PH形成的关键环节。本研究应用低氧及野百合碱（MCT）诱导的两种动物肺高压模型；低氧及血小板源性生长因子（PDGF-BB）刺激PASMC，发现低氧及MCT诱导的PH动物肺组织活化T细胞核因子c1（NFATc1）蛋白水平增加，且主要发生在肺动脉平滑肌层；给予DHA灌胃后可抑制NFATc1的表达增加；且DHA可显著降低MCT诱导的PH大鼠平均肺动脉压，右心室肥厚及肺血管重塑。在细胞水平，低氧及PDGF-BB刺激均可诱导NFATc1的蛋白表达及核转移增加。低氧可诱导PASMC由收缩型向增殖型转变，而DHA可抑制低氧诱导的PASMC的表型转变；过表达NFATc1可逆转DHA的抑制表型转变效应。PDGF-BB刺激可触发PASMC内质网应激，诱导NFATc1的总蛋白增多及核转移增加，促进PASMC增殖；DHA可抑制PDGF-BB诱导的内质网应激，抑制NFATc1表达及激活，减少PASMC的增殖。总之，本研究从动物及细胞水平，应用不同肺高压动物模型及细胞刺激因素发现DHA通过抑制PASMC的NFATc1的表达及激活，抑制PASMC表型转变，减少其增殖，改善肺血管重构，发挥抗肺高压作用。