组织蛋白酶D在血管内皮损伤中的作用及其机制研究

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in China and around the world. Dysfunction of endothelial cells plays a key role in the initiation and development of CVD. Cathepsin D (CTSD), one kind of aspartic acid hydrolase, involves in autophagy and apoptosis and regulates cell survival and differentiation. Many stimulating factors such as metabolic products, hormones, and growth factors can affect the expression and activity of CTSD. Recent studies imply an important role of CTSD in CVD. For the first time, we found that CTSD expression decreased with increasing gradient concentrations of advanced glycation end products in cultured human umbilical vein endothelial cells (HUVECs). We also demonstrated that overexpression of CTSD could relieve the injury of HUVECs. Furthermore, results from genechip and western blot indicated that CTSD might play a protective role through interaction with GADD45A. The current project aims to clarify the role of CTSD in dysfunction of HUVECs and its potential mechanism. This project will provide potential target for prevention/treatment of CVD such as atherosclerosis, hypertension and diabetic angiopathies.

心血管疾病(CVD)是人类健康的主要威胁。血管内皮细胞功能紊乱是在CVD的发生发展中起到关键作用。组织蛋白酶D(CTSD)是属于天冬氨酸水解酶，参与调节凋亡和自噬等多种细胞过程，在维持细胞生存和分化等方面具有重要的调控作用。许多刺激因子如新陈代谢产物、激素、生长因子等都能影响CTSD的表达及活性。最新研究表明，CTSD与心血管疾病有关。我们首次发现，随着内皮细胞损伤的加重，CTSD的表达逐渐下降，过表达CTSD能缓解受损的内皮细胞功能。人基因表达谱芯片以及Western blot结果提示CTSD可能通过下调GADD45A的表达，进而缓解内皮细胞损伤。本课题旨在阐明这一科学假设并探讨CTSD在内皮细胞损伤中的作用及其可能的机制。本项目的阐明可能为动脉粥样硬化、高血压和糖尿病血管病变等重大疾病的预防和治疗提供新的重要思路。

我们在已结题项目“组织蛋白酶D在血管内皮损伤中的作用及其机制研究”中，明确了CTSD对HUVEC增殖、迁移、凋亡、自噬和细胞周期的影响。明确在AGEs诱导HUVEC损伤中的凋亡、自噬、细胞周期调控通路的作用。我们进一步延伸了项目内容，获得了新的生长点。进一步探索了E3泛素化连接酶Smurf2结合并调控PARP1的稳定性抑制氧化应激诱导的HUVEC凋亡的机制。明确了E3泛素化连接酶WWP2在调节氧化应激HUVEC损伤中对Septin4泛素化和降解的作用。明确了E3 泛素化连接酶Fbw7通过结合Mcl-1参与氧化应激诱导的H9c2细胞损伤的机制。本项目结果的阐明可能为动脉粥样硬化、高血压和糖尿病血管病变等重大疾病的预防和治疗提供新的重要思路。