血管过氧化物酶1促进冠脉侧支循环形成及机制研究

Although interventional therapy or bypass surgery is the effective treatment modality for patients with coronary heart disease (CHD), there is a still high postoperative restenosis rate and both procedures are not indicated for some patients. Well-developed collateral circulation is definitely beneficial for improving either symptoms or outcomes of the CHD patients. Hence, investigating the regulatory mechanism for formation of the coronary collateral circulation, and then actively promoting the opening and development of the coronary collaterals for reconstruction of the patients’ own blood supply may be the most promising solution. Vascular peroxidase 1 (VPO1) that was firstly found and identified by our group is an oxidative stress-inducing factor, and the VPO1/HOCl pathway plays an important role in mediating oxidative stress in cardiovascular system. As oxidative stress is one of the important influential factors for collateral formation, we conducted preliminary studies to investigate the relationship between VPO1 and collateral formation, and the results showed a significant correlation between them. Thus, in this project, we plan to comprehensively analyzed and elucidate the action and mechanism of VPO1 in regulating coronary collateral circulation development from of clinical data analysis, cell experiments, and in vivo animal models, so as to provide new prospects in the treatment and drug development of CHD.

尽管介入与搭桥手术是冠心病患者的有效治疗手段，但仍存在较高的术后再狭窄以及部分患者无法实施的问题。侧支循环的形成对于冠心病患者症状及预后的改善均有明确的益处，因此，探讨冠脉侧支循环形成的调控机制，主动促进冠脉侧支循环的开放与建立，实现患者自身血运重建可能是最有希望的解决途径。血管过氧化物酶1（VPO1）是本课题组首次发现并证实的一种氧化应激诱导因子，VPO1/HOCl途径在介导心血管系统氧化应激中发挥重要作用。由于氧化应激是侧支循环的形成的重要影响因素，我们初步研究了VPO1与侧支循环形成的关系，结果提示了两者存在密切的相关性。因此，本研究拟通过临床分析、细胞与动物实验，全面分析并探明VPO1在冠脉侧支循环调控中的作用及机制，为冠心病的治疗和新药的研发提供新的思路。

良好冠脉侧支循环的形成对于改善冠心病患者的症状及预后均有重要的临床意义，因此，探明冠脉侧支循环形成的调控机制，实现患者自身血运重建可能是冠心病患者最有希望的防治策略之一。血管平滑肌细胞（VSMCs）的表型转变在冠脉侧支循环形成过程中发挥关键作用，本项目以VPO1/HOCl途径介导的氧化应激为切入点，探讨了其调控VSMCs表型转变进而影响侧支循环形成的作用机制。本项目的研究结果发现，VPO1/HOCl通过KLF4通路调控VSMCs表型转化，并且也验证了VPO1通过激活H2O2/VPO1/HOCl/ERK/KLF4信号通路调控VSMCs的表型转化，从而影响腹主动脉瘤的发生发展过程，我们还证明了VPO1通过NOX4/VPO1/HOCl/NF-κB通路调控肺动脉平滑肌细胞（PASMCs）的增殖、凋亡抵抗和迁移，从而影响肺动脉高压的发生发展过程。我们一系列的研究结果充分证明了VPO1/HOCl途径调控的氧化应激效应在调控VSMCs表型转变过程中扮演重要作用，进而可能影响腹主动脉瘤及侧支循环的发生发展。此外，本项目还进行了其它相关研究，发现VPO1/HOCl途径在血管内皮功能不全和心肌纤维化中也发挥重要作用、miR-15b-5p通过AKT3通路及NFAT5/MCP-1通过招募单核细胞调控侧支动脉的形成、血管内皮细胞中miR-199异常升高所致的前列环素合酶（PTGIS）失活是冠心病患者硝酸甘油耐受的关键机制。这些研究成果有望为以VPO1为干预靶点的自主侧支循环的形成及缺血性心脏病的防治提供新的理论依据和新思路。