Cathepsin L/V通过TLR4/Caveolin-1诱导衰老血管舒张功能障碍的机制研究

Cardiovascular disease is the number one cause of death for the elder people. Endothelium-dependent relaxation dysfunction is essential at the early stage of aging-related vascular disease. Cysteine Cathepsin L/V (CatL/V) contributes to many cardiovascular diseases. However, it is still unclear whether CatL/V is involved in the regulation of endothelium-dependent relaxation. Striking new findings from our preliminary studies indicate that the expression and activity of CatL were increased in aging mouse aorta. And young mouse aorta endothelium-dependent relaxation function was damaged, resulting from over expression of CatL by adenovirus. Our lab’s latest studies identified that CatL/V is interacted with TLR4. Meanwhile TLR4 can regulate the expression of Caveolin-1 (CAV-1). Recent studies demonstrate CAV-1 contributes to endothelium-dependent relaxation dysfunction through inhibiting eNOS/NO pathway. These intriguing findings form the basis for our central hypothesis that CatL/V induces aging vasodilation dysfunction through TLR4/Caveolin-1 pathway. This study will focus on the role of CatL/V in aging-related endothelial dysfunction and its molecular mechanism at clinical, animal, cellular and molecular level. We hope to provide theoretical basis for the prevention strategy of cardiovascular diseases caused by aging-related endothelial dysfunction.

心血管疾病是危害老年人健康的头号杀手，内皮依赖的血管舒张功能障碍是衰老相关血管疾病的早期关键环节。半胱氨酸组织蛋白酶Cathepsin L/V（CatL/V）参与众多心血管疾病的调控，是否参与衰老血管功能障碍调控目前尚不清楚。申请人前期实验发现，衰老小鼠血管CatL的表达和活性均升高，青年小鼠主动脉上过表达CatL损伤内皮依赖的血管舒张功能。申请人所在实验室最新研究报道CatL/V与TLR4存在相互作用，TLR4可调控小窝蛋白-1(Caveolin-1, CAV-1)表达。结合文献报道CAV-1可通过负向调控eNOS/NO导致内皮依赖的血管舒张功能障碍，因此推测CatL/V可能通过TLR4/CAV-1通路诱导衰老血管舒张功能障碍。本课题拟在临床、动物、细胞及分子水平探讨CatL/V在衰老血管舒张功能障碍中的作用及分子机制，为衰老相关内皮功能障碍所致心血管疾病的防治提供理论依据。

心血管疾病是危害人类健康的头号杀手，而血管衰老是老年人发生心血管疾病的关键环节之一。半胱氨酸组织蛋白酶Cathepsin L/V（CatL/V）参与众多心血管疾病的调控，本项目利用动物与细胞实验研究，结合腺病毒转染技术和工具药对CatL/V与内皮细胞、血管衰老的关系进行了较深入的研究，主要发现如下：1.在衰老小鼠主动脉和H2O2诱导的衰老内皮细胞中，CatL/V表达下降；2.使用腺病毒过表达CatV可抑制H2O2诱导的内皮细胞衰老，并提高细胞增殖和迁移能力；3.通过转录组测序发现CatV可能通过ALDH1A2调控内皮细胞衰老；4.进一步使用ALDH1A2的公认下游因子RA发现Cat V可通过ALDH1A2-AKT/ERK通路调控内皮细胞衰老。这些发现提示CatV是调控内皮细胞衰老的关键分子，为今后进一步研究CatL/V在血管衰老中的作用打下基础，为防治老年相关血管疾病提供了新思路。