小鼠Enho/Adropin完全及血管内皮细胞条件性敲除对增龄性血管衰老的影响及其机制

血管衰老是动脉粥样硬化（AS）等增龄性心血管疾病的主要危险因素。目前缺乏有效延缓血管衰老的治疗干预靶点/药物。我们前期发现，能量稳态相关基因（Enho）编码的蛋白Adropin可以减轻小鼠AS；Enho基因敲除导致老年小鼠主动脉AS、管腔扩大、动脉僵硬及衰老标志物表达加重。因此我们提出假说，Enho/Adropin可能是延缓血管衰老的潜在治疗干预靶点/药物。本项目使用Enho基因完全和内皮细胞条件性敲除的年轻和老年模型，以及过氧化氢诱导人脐静脉内皮细胞（HUVECs）衰老模型，使用siRNA干扰下调HUVECs Enho基因表达；采用组织病理学、RT-PCR、Western blot和血管功能学等技术，明确Enho基因缺失和补充外源性Adropin蛋白对主动脉血管衰老的影响；细胞实验中应用信号蛋白阻断剂明确抗衰老SIRT1、JunD信号通路的作用。本项目将为延缓血管衰老提供新的策略。

Vascular aging is a major risk factor of age-related cardiovascular diseases, including atherosclerosis. Nowadays there are no effective therapeutic targets or agents to delay vascular aging. Our previous study showed that the protein adropin encoded by energy homeostasis-associated gene (Enho) may protect against the progression of aortic atherosclerosis in mice, and compared with age-matched wild-type mice, elder mice with Enho knockout (AdrKO) or conditional deletion of Enho in vascular endothelial cells may present more severe aortic atherosclerosis, lumen enlargement and arterial stiffness, and may increase the expression of aging markers in aortas. Therefore, we hypothesize that Enho/Adropin may be a potential therapeutic target/agent for delaying vascular aging. In this study, we use two animal models mentioned above (both young and elder) and hydrogen peroxide-induced cell senescence model in human umbilical vein endothelial cells (HUVECs), and the siRNA interference will be used to down-regulate Enho expression in HUVECs. Histopathology, RT-PCR, Western blot and vascular function test will be performed to clarify the effects of Enho/Adropin deletion and adding ectogenic Adropin on vascular aging. The role of anti-aging signaling pathways SIRT1 and JunD in senescent HUVECs will be established by using signaling protein blockers. This study will provide a new strategy to delay vascular aging.