动脉粥样硬化是许多心血管疾病的重要成因。大量的实验证据和临床资料表明，炎症反应在动脉粥样硬化的发生发展过程中起重要作用，其机制与巨噬细胞等炎性细胞浸润、大量炎性因子分泌、平滑肌细胞迁移及泡沫细胞生成等密切相关。我们的前期实验结果表明，敲除CD38基因可使高脂饮食诱导的ApoE基因敲除小鼠动脉粥样硬化损伤明显加重；CD38基因敲除小鼠的原代培养巨噬细胞TLR4表达及LPS刺激巨噬细胞诱导的炎性因子分泌明显高于野生型小鼠。结果表明CD38基因缺失可显著促进动脉粥样硬化损伤。本项目旨在探讨CD38及其调控的巨噬细胞对动脉粥样硬化形成的影响，并阐明其介导的TLR4-NFκB、NOX-ROS-ERK、SIRT1-FOXO1等信号通路在动脉粥样硬化中的作用及其机制。显然，阐明CD38基因对动脉粥样硬化形成的保护作用及其分子机制，将为寻找有效防治动脉粥样硬化等心血管疾病的新靶点提供线索和实验依据。

Atherosclerosis is an important cause of many cardiovascular diseases. Numerous experimental evidence and clinical resources indicated that the inflammation plays an important role during the development of atherosclerosis. The involved mechanism is closely related with the inflammation cells infiltration, cytokine secretion, smooth muscle cells migration and foam cells formation. Our preliminary experimental results showed that the disruption of gene CD38 could result in more severe injury in atherosclerosis model induced by high fat diet in ApoE-/- mice compared with deficiency of ApoE gene alone. The mRNA expression of gene TLR4 in primary cultured macrophages from CD38-/- mice and the secretion of inflammation cytokine with LPS stimulation in the macrophages were much higher than that detected in WT mice. Our results indicated that the CD38-deficiency significantly enhances injury of atherosclerosis. This proposal is aimed to investigate the effects of CD38 gene and CD38-mediated macrophages on atherosclerosis and, further to clarify the exact functions and molecular mechanisms of CD38 gene in the signal pathways such as TLR4-NFκB、NOX-ROS-ERK、SIRT1-FOXO1 which are related with inflammation. Obviously, elucidating the function and protective mechanism of the CD38 gene on atherosclerosis formation would provide clues and experimental basis for looking for new targets of efficiently preventing and curing atherosclerosis and other cardiovascular diseases.

研究表明，炎症反应在动脉粥样硬化的发生发展过程中起重要作用，其机制与巨噬细胞介导的炎性细胞浸润、炎性因子分泌、平滑肌细胞迁移及泡沫细胞生成等密切相关。本课题旨在探讨CD38对高脂饮食诱导ApoE-/-小鼠动脉粥样硬化形成的影响，并阐明CD38介导的巨噬细胞TLR-NF-κB、SIRT1-FOXO1以及NOX-ROS等信号通路在动脉粥样硬化发生发展过程中的作用及其分子机制。我们的结果证明，CD38缺失可加重高脂饮食诱导的动脉粥样硬化损伤，其机制主要与其促进巨噬细胞向动脉粥样硬化斑块区域的迁移，加重局部炎症反应有关。本课题的主要发现有：1）敲除CD38基因可显著加重高脂饮食诱导ApoE-/-小鼠动脉粥样硬化损伤：结果显示虽然敲除CD38基因可使ApoE基因敲除鼠的血脂（包括胆固醇、甘油三酯以及低密度脂蛋白）水平明显降低，但CD38/ApoE双基因敲除鼠表现为动脉粥样硬化损伤明显加重。尤其重要的是，ApoE-/-鼠的动脉粥样硬化斑块中CD38的高表达区伴随着巨噬细胞侵润缺失，提示CD38缺失可促进巨噬细胞的侵润，加重动脉粥样硬化损伤。2）CD38缺失可明显激活巨噬细胞的TLR-NF-κB信号通路：我们的结果表明，CD38基因缺失可使转录因子FOXO1去乙酰化，促进后者的核转移，进而促进炎症相关蛋白MCP-1、TLR4、NF-κB的表达，并可增强LPS刺激诱导的M1型细胞因子TNF-α、IL-1β等促炎蛋白的分泌，而对M2型细胞的抑炎因子如IL10、IFN等无明显影响。此外，CD38基因缺失还可促进单核细胞趋化因子受体CCR2蛋白的表达，提示CD38可能通过抑制TLR4-NF-κB信号途径而发挥其抗动脉粥样硬化作用。3）CD38缺失可显著抑制巨噬细胞TLR2的表达，进而加重动脉粥样硬化斑块区域的炎症反应：结果表明，敲除CD38基因可明显抑制巨噬细胞TLR2的mRNA和蛋白表达，并证明由CD38缺失介导的Sirt1激活可明显抑制巨噬细胞TLR2的表达，而这一作用是受CD38-Sirt1-NF-kB信号通路调控。4）CD38缺失可明显加速内皮细胞增殖和新生血管形成，进而促进斑块组织形成：结果提示CD38基因缺失可通过增加胞内NAD浓度促进内皮细胞增殖及显著促进新生血管形成，进而加重损伤，并证明CD38缺失介导的这一作用与其抑制内皮细胞的VEGF-NOS信号通路有关。