Omentin-1调控血管损伤后再内皮化进程及机制研究

The higher occurrences of in-stent restenosis (ISR) in obese patients after percutaneous coronary intervention (PCI) is a clinical puzzle. Delayed reendothelialization resulted from the depletion of endothelial progenitor cells (EPCs) is an important pathophysiological mechanism, in which adipocytokines play important roles. Omentin-1 is a novel adipocytokine and correlate with coronary heart disease (CHD), whose downstream protein osteoprotegerin (OPG) plays crucial roles in regulating EPCs functions. Furthermore, our previous studies demonstrated not only omentin-1 can promote EPC adhesion to EC, migration and inhibit angiogenesis in vitro in EC, but also can cause a reduction of neointima formation in balloon injury of carotid artery. Base on the newest research advances and our previous works, we hypothesis that omentin-1 influence ISR and reendothelialization via OPG pathway to regulate EPC functions in obese patients after PCI. This study will clarify the associations between omentin-1 and ISR in obese patients as well as the effects and mechanisms of omentin-1 regulate EPC functions, in clinical samples and cell experiments. Besides, we will further confirme the promoting effects of omentin-1 in EPC-mediated reendothelialization progresses and mechanisms. Our study will provide an alternative strategy in prevention and cure, novel functional stent of ISR.

肥胖患者PCI术后再狭窄率高是困扰临床的难题，内皮祖细胞（EPC）功能降低导致的再内皮化延迟是再狭窄形成的重要病理生理机制，脂肪因子在这一进程中发挥重要作用。Omentin-1是一种新发现的与冠心病相关的脂肪因子，其下游蛋白OPG广泛参与了对EPC的调控，同时我们前期的预实验也发现Omentin-1不仅可以促进EPC与内皮细胞的粘附、迁移和抑制血管新生，还能逆转球囊损伤导致的内膜新生。结合国内外研究进程和我们前期的工作基础，我们提出假设：肥胖患者中Omentin-1通过OPG通路调控EPC功能，进而影响PCI术后再内皮化进程和再狭窄形成。本研究拟从临床样本和细胞水平阐明Omentin-1与肥胖患者PCI术后再狭窄的关系和对EPC功能的调控作用及机制，同时从动物模型上进一步确证Omentin-1促进EPC介导的再内皮化进程及机制。本研究有望为再狭窄的防治以及新型功能化支架的开发提供新的策略。

肥胖患者PCI术后再狭窄率高是困扰临床的难题，内皮祖细胞（EPC）功能降低导致的再内皮化延迟是再狭窄形成的重要病理生理机制。本项目从内脏脂肪与“肥胖悖论”的角度出发，通过动物实验和细胞实验的研究，重点探讨了内脏脂肪因子Omentin-1通过调控EPC的功能影响血管损伤后再内皮化进程及可能机制。本项目的研究结果表明，Omentin-1过表达的EPC可明显抑制颈动脉球囊损伤大鼠的内膜新生，还可明显促进EPC的招募、归巢和粘附，其机制可能与CXCR4/AKT通路有关。此外，在本项目资助下，我们还发现：（1）Omentin-1与严重冠脉狭窄的冠心病患者良好冠脉侧枝循环相关，其机制可能与Omentin-1通过抑制Notch1通路活化从而调控巨噬细胞M2型极化有关；（2）循环EPC的数量和功能影响绝经后高胆固醇血症女性和绝经后体重超重的女性心血管发病风险。这些研究成果为PCI术后再狭窄和其它心血管疾病的防治提供了新的理论依据和潜在靶点。