组蛋白去甲基化酶JMJD2A在肺动脉高压中的作用及机制研究

Pulmonary arterial hypertension (PAH) is a progressive disease. Despite the availability of prostacyclin analogs,endothelin receptor antagonists and phosphodiesterase-5 inhibitors, pharmacologic treatment of PAH continues to have significant limitations. Pulmonary arterial smooth muscle cells (PASMCs) proliferation promote pulmonary arterial remodeling, which plays a critic role in PAH. Few studies had focused on histone modification in epigenetic regulation of PASMCs proliferation. Knockdown of JMJD2A, a histone demethylase, inhibits proliferation of many kinds of cancer cells and vascular smooth muscle cells and ameliorates cardiac hypertrophy. However, so far there is no report about the role of JMJD2A in PAH. The present research is aimed at exploring the role of JMJD2A in PAH and pulmonary arterial remodeling and investigating the role of JMJD2A in proliferation and migration of PASMCs. Further, this research attempts to clarify the epigenetic regulation mechanism of JMJD2A in PASMCs proliferation. Our research is likely to provide a new therapeutic target for PAH.

肺动脉高压是一种恶性进展性疾病，现有靶向治疗主要针对肺血管收缩这一环节，不能有效阻止病情进展。肺血管重塑是促使肺动脉高压发生、发展的重要原因。抑制肺动脉平滑肌增殖可阻止肺血管重塑，是寻找肺动脉高压治疗新靶点的关键。既往以组蛋白修饰为切入点，针对肺动脉平滑肌增殖的表观遗传调控研究较少见。组蛋白去甲基化酶JMJD2A通过表观遗传调控，在促进多种肿瘤细胞增殖、迁移，血管平滑肌增殖、心肌肥厚方面发挥强大作用。然而，JMJD2A在肺动脉高压中的作用尚无报道。本课题拟研究JMJD2A在肺血管重塑及肺动脉高压中的作用；JMJD2A对肺动脉平滑肌增殖、迁移的影响；并且，进一步在分子水平探讨JMJD2A发挥作用的表观调控机制。此研究，可为肺动脉高压的治疗提供新的靶点。

肺动脉高压是一种恶性进展性疾病，现有靶向治疗主要针对肺血管收缩这一环节，不能有效阻止病情进展。肺血管重塑是促使肺动脉高压发生、发展的重要原因。抑制肺动脉平滑肌增殖可阻止肺血管重塑，是寻找肺动脉高压治疗新靶点的关键。既往以组蛋白修饰为切入点，针对肺动脉平滑肌增殖的表观遗传调控研究较少见。组蛋白去甲基化酶JMJD2A通过表观遗传调控，在促进肿瘤细胞增殖、迁移，血管平滑肌增殖、心肌肥厚方面发挥强大作用。然而，JMJD2A在肺动脉高压中的作用尚无报道。本课题研究JMJD2A在肺血管重塑及肺动脉高压中的作用，探索其机制。首次发现，JMJD2A抑制剂2,4-PDCA可以抑制肺血管重塑，在肺动脉高压中发挥保护作用。机制方面，2,4-PDCA可通过抑制JMJD2A，调控细胞周期蛋白、凋亡蛋白的表达，从而抑制肺动脉平滑肌增殖与迁移。此外，p53已被证实在肺动脉高压中发挥保护作用。而本研究发现p53可在转录水平抑制JMJD2A的表达。此研究结果为肺动脉高压的治疗提供新的靶点。