解偶联蛋白2在血管再狭窄中的作用及分子机制

Restenosis has been related to oxidative stress-induced proliferation and migration of vascular smooth muscle cells (VSMC). Uncoupling protein 2 (UCP2) is an important molecule in the regulation of vascular superoxide anion (O2-) production, and the transient receptor potential A1 (TRPA1) channel is the main sensor of O2-. Our previous study demonstrated that the UCP2 plays a protective role in vascular dysfunction and remodeling. However, the role of UCP2 in vascular restenosis is still unclear. This project intends to study the role of UCP2 in vascular restenosis by using mechanical endothelial injury-induced restenosis or in-stent restenosis animal models in C57BL/6J mice and ApoE-/- mice with loss of function or gain of function of UCP2. TRPA1-/- mice will be used to study the role of TRPA1 in downstream pathways involved in UCP2-regulated O2- production. We will also detect the intracellular calcium signal, the expression of nitric oxide synthase and nitric oxide levels to explore the mechanisms regulating VSMC proliferation and migration. The aim of this project is to clarify the role of UCP2 in intima hyperplasia and vascular restenosis and its molecular mechanism, and to provide a new target for the prevention and treatment of in-stent restenosis.

血管再狭窄与氧化应激反应诱导的血管平滑肌细胞（VSMC）增殖和迁移有关。解偶联蛋白2（UCP2）是血管组织中调控超氧阴离子(O2?）产生的重要分子，而瞬时受体电位A1（TRPA1）通道是O2?的主要感受器。申请人在青年基金项目研究中证实了UCP2对血管功能障碍和结构重构具有保护作用，但UCP2在血管再狭窄中的作用尚不清楚。本项目拟采用UCP2-/-小鼠和转基因小鼠作为工具，采用C57BL/6J小鼠和ApoE-/-小鼠作为研究对象，构建内皮损伤和支架植入术后血管再狭窄两种动物模型，通过双基因敲除等技术探讨UCP2在血管再狭窄中的作用。拟采用TRPA1-/-小鼠揭示其在UCP2调控的O2?下游所发挥的作用，并通过检测细胞内钙信号、一氧化氮合酶表达、一氧化氮水平探讨其调控VSMC增殖和迁移的机制。旨在阐明UCP2在内膜增生及血管再狭窄中的作用及其分子机制，为支架植入术后再狭窄的防治提供新靶点。

血管损伤后内膜增生是支架植入术后血管再狭窄的病理基础。本项目在离体细胞、组织和活体小动物及大动物中研究了解偶联蛋白2（UCP2）在血管损伤后平滑肌细胞增殖、新生内膜形成和血管再狭窄中的作用及分子机制。结果发现UCP2在损伤血管中表达降低，UCP2表达缺失可加重血管损伤后血管平滑肌细胞增殖和内膜增生，过表达UCP2可抑制血管平滑肌细胞增殖，抑制血管损伤后内膜增生和小型猪冠状动脉支架植入术后再狭窄。本研项目研究结果为血管再狭窄的防止提供了新思路。