内源性GTPCH I/BH4 通路在高血压血管再狭窄中的作用及机制研究

Endothelial dysfunction contributes to diverse vascular disease processes including hypertension and angioplasty-induced restenosis. Studies have shown that both EC and EPC dysfunction are independent predictors of cardiovascular mortality including hypertension. Because nitric oxide (NO) produced from eNOS is critically involved in the normal function of both EC and EPC, the loss of its protective actions is a cardinal feature of EC and EPC dysfunction. Evidence also indicates that eNOS is a bi-functional enzyme that can become “uncoupled” toproduce superoxide anion (O2-) instead of NO when its essential cofactor tetrahydrobiopterin(BH4) is oxidized by reactive oxygen species (ROS). The deoxycorticosterone acetate(DOCA)-salt hypertension is such a typical model featuring eNOS uncoupling. Inasmuch,eNOS uncoupling has a major impact on the redox state and function of vascular tissues.Therefore, it is extremely important to understand the dynamic regulation of BH4 synthesison both EC and EPC function in vascular disease in vivo. GTP cyclohydrolase I (GTPCH I)is the rate-limiting enzyme for de novo synthesis of BH4. Remarkably little is known about how GTPCH I influences restenosis and EPC function as well as the regulatory mechanisms for its expression and activity in vivo. This project will focus on how the deregulation of the endogenous GTPCH I/BH4 pathway influences EC and EPC function in vivo, thus filling a significant gap in such knowledge. We hypothesize that O2- contributes to GTPCH I deficiency and subsequent EC and EPC dysfunction in hypertension and restenosis, which may be rescued by endothelial-specific GTPCH I-mediated de novo BH4 synthesis.

血管内皮功能障碍是导致高血压等多种心血管疾病发生的重要机制。研究显示内皮细胞（EC）及内皮祖细胞(EPC)的功能障碍是导致心血管事件的独立危险因素。而eNOS合成NO的过程对维持EC及EPC功能正常有着至关重要的作用。当辅酶四氢生物蝶呤（BH4）缺乏时，eNOS发生 “脱耦联” ，不能生成具有生物活性的NO，而是产生超氧阴离子O2-进而损伤内皮功能，加剧血管氧化应激损伤，因此了解体内BH4对EC及EPC功能的影响具有极其重要的意义。GTP环水解酶（GTPCH I）是BH4从头合成的限速酶，本课题组利用DOCA-盐高血压模型，发现GTPCH I影响血管内皮功能，但是GTPCH I/BH4通路如何影响高血压血管损伤再狭窄，以及其在体内的表达和活性的调节的机制尚未阐明。本课题拟进一步深入研究内源性GTPCH I/BH4 通路在高血压血管内皮损伤及对EPC功能影响中的作用及机制，进以寻找新的改善血管内皮功能的治疗靶点，为临床心血管疾病的治疗提供新的理论基础和实验依据。

血管内皮功能障碍是导致高血压等多种心血管疾病发生的重要机制。研究显示内皮细胞（EC）及内皮祖细胞(EPC)的功能障碍是导致心血管事件的独立危险因素。而eNOS合成NO的过程对维持EC及EPC功能正常有着至关重要的作用。我们的研究发现：当eNOS辅助因子四氢生物蝶呤（BH4）缺乏时，eNOS发生 “脱耦联” ，不能生成具有生物活性的NO，而是产生超氧阴离子O2-进而损伤内皮功能。DOCA盐高血压小鼠具有eNOS “脱耦联”的特点。由于eNOS发生“脱藕联”会加剧血管氧化应激损伤，因此体内BH4对EC及EPC功能的影响具有极其重要的意义。GTP环水解酶（GTPCH I）是BH4从头合成的限速酶。本课题发现：GTPCH I影响血管再狭窄和高血压，为血管损伤提供了细胞治疗或基因治疗的可行性。