去泛素化酶BRCC36在低氧诱导的肺血管重构中的作用及机制

Chronic hypoxia-induced and (or)-aggravated pulmonary artery hypertension has become a major cardiovascular disease affecting human health. However, the pathogenesis of hypoxia-induced PAH formation remains unclear so far. We recently have demonstrated that activation of atrial natriuretic peptide (ANP)-cGMP-PKG pathway effectively prevented chronic hypoxia-induced PAH and treatment with cGMP significantly increase the deubiquitylating enzyme BRCC36 expression in cultured rat pulmonary artery smooth muscle cells. As we know, there are not related studies to show the effects of BRCC36 on chronic hypoxia-induced pulmonary vascular remodeling and PAH formation until now. Using the cultured rat pulmonary artery smooth muscle cells, in vivo studies and multiply modern molecular biologic methods, the presently proposed project aims to illustrate that 1) the effect of BRCC36 in the ANP-cGMP-PKG signaling pathway; 2) the effect and molecular mechanism of BRCC36 on hypoxia-induced the proliferation, migration and phenotypic switching of pulmonary artery smooth muscle cells under hypoxia condition; 3) we have successfully constructed the SMA22α-BRCC36 transgenic mice which specifically over-expressed BRCC36 in smooth muscle cells. Lastly, using the novel mouse model, we will illustrate the functional significance of BRCC36 in chronic hypoxia-induced PAH and pulmonary vascular remodeling in vivo. Collectively, these results will provide some new insights and novel molecular drug targets for the prevention and treatment of pulmonary artery hypertension.

长期缺氧诱发或加重的肺动脉高压（PAH）目前已成为影响人类健康的一种重大心血管疾病，但其发病机制至今尚未完全清楚。我们近来证实，激活ANP-cGMP-PKG通路可有效抑制缺氧诱导的PAH形成，而且cGMP处理可直接上调肺动脉平滑肌细胞内去泛素化酶BRCC36表达，但BRCC36是如何参与调控低氧诱导的肺血管重构及PAH形成，目前国内、外尚未见有相关报道。本项目使用肺动脉平滑肌细胞作为研究模型，结合整体动物实验，利用多种实验技术试图阐明1）BRCC36是如何参与调节ANP-cGMP-PKG信号通路？2）在缺氧条件下，BRCC36对肺动脉平滑肌细胞增殖、迁移及表型转换的影响及其分子机制；3）最后利用我们新构建的平滑肌细胞特异性过表达BRCC36转基因小鼠，在整体水平揭示BRCC36在缺氧诱导的肺血管重构及PAH形成中的作用，从而为研发有效防治PAH的治疗策略提供新的思路和分子药物干预靶标。

肺动脉高压是以肺循环阻力升高为特征的进行性发展的一种致死性心血管疾病。在众多致病因素中，缺氧是诱发高原型肺高压、各种先天型心脏病、慢性心力衰竭、慢性阻塞性肺疾病以及新生儿肺高压发病的一个主要因素。然而目前临床治疗药物对缺氧诱导的肺动脉高压疗效则十分有限。因此，进一步阐明PAH的发病机制并探讨新的治疗策略具有重大的临床意义和社会意义。先前我们课题组发现去泛素化酶BRCC36可参与负性调控TGF-β1-Smad3通路，但BRCC36在低氧诱导的肺动脉高压发生机制中的作用并不清楚。本项目利用体外培养的分离培养成年大鼠PASMC模型和血管平滑肌细胞特异性过表达BRCC36的转基因小鼠，采用多种现代分子生物学实验技术研究证实：缺氧状态下氧链糖基化修饰（O-GlcNAc）修饰水平的变化有可能参与缺氧诱导的肺动脉高压形成，这种不同性别对缺氧条件下组织内O-GlcNAc修饰水平的调节的二态性很可能与不同性别个体对缺氧诱导的肺动脉高压、右室肥厚形成的易感性有关；其次，低氧和BMP通路的激活可促进肺动脉平滑肌细胞内去泛素化酶BRCC36蛋白的表达，而过表达BRCC36通过则可减轻低氧状态下经典抗肺动脉高压BMP-PPARγ -apoE通路的抑制，同时抑制PDGE-BB诱导的肺动脉平滑肌细胞异常增殖和迁移活化，抑制低氧诱导的促肺动脉高压形成TGF-β1-Smad3通路的活化。最后在体内，研究发现平滑肌细胞特异性过表达BRCC36有助于防止低氧诱导的肺血管的增殖以及促进低氧诱导的肺组织中的BMP信号通路的激活，从而改善低氧诱导的肺动脉高压和肺血管重构。该研究为寻找以BRCC36为靶点的肺动脉高压治疗新型策略提供新的思路和分子药物干预靶标。

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