HDL通过SR-BI调节造血干细胞抑制动脉粥样硬化的作用和机制研究

项目名称： HDL通过SR-BI调节造血干细胞抑制动脉粥样硬化的作用和机制研究

项目编号： No.81470566

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 冯英梅

作者单位： 首都医科大学

项目金额： 73万元

中文摘要： 目前大多数研究发现高密度脂蛋白(HDL)通过抑制炎症细胞侵入动脉粥样硬化(As)病变血管而起到抗As作用,但对HDL是否、如何抑制炎症细胞的祖/前体细胞,即造血干/前体细胞(HSPC)从而减少炎症细胞数量、抗As尚不明确。我们新近发现①注射重组HDL明显抑制小鼠HSPC的增殖进而减少炎症细胞生成；②HSPC上表达HDL的受体SR-BI,高脂血症的SR-BI缺陷小鼠其HSPC增生、炎症细胞增多、As加重。据此，我们提出HDL通过SR-BI抑制HSPC增殖、减少炎症细胞生成从而减轻As科学假说。在本课题中，我们将用高血脂的SR-BI缺陷小鼠模型探索①HDL和SR-BI调节HSPC增殖的主要分子机制，着重于SR-BI对HSPC磷酸化通路、活性氧生成和转录因子的影响；②抑制HSPC增殖对As进程的影响。该课题旨在揭示HDL通过调控HSPC来抑制炎症和As,可望为冠心病治疗提供新的思路。

中文关键词： 高密度脂蛋白；造血干细胞；SR-BI；动脉粥样硬化；炎症反应

英文摘要： Inflammatory cells in atherosclerotic plaque are exclusively derived from hematopoietic stem/progenitor cells (HSPCs). Recently, we and Yves-Charvet demonstrated that infusion of reconstituted HDL (rHDL) or lipid poor human apolipoprotein A-I (apoA-I) inhibits hematopoietic stem/progenitor cells (HSPCs) proliferation in hypercholesterolemic Abca1-/-Abcg1-/- mice and C57BL/6 mice, therefore, limiting white blood cell expansion in the peripheral blood (PB). In patients with coronary heart disease, we identified that HDL levels were negatively correlated with white blood cell count and HSPC frequency in PB (unpublished data). In addition, by flow cytometry, we demonstrated that the HDL receptor, scavenger receptor type BI (SR-BI), is expressed on murine and human HSPC. SR-BI is expressed on hepatocytes and facilitates selective cholesterol ester uptake from HDL. Previously, others and we have illustrated the anti-atherosclerotic function of SR-BI in different mouse models. Moreover, SR-BI deficiency is associated with impaired HDL function, intracellular cholesterol accumulation and increased oxidative stress. This led us to hypothesize that SR-BI deficiency impairs the regulation of HDL on HSPC, modulates Akt and MAPK phosphorylation and leads to increased reactive oxygen species production in HSPC, resulting in enhanced HSPC proliferation and differentiation and accelerated atherosclerosis. This study aims to investigate how HDL and SR-BI modulate HSPC proliferation and differentiation in the treatment of atherosclerosis.Ultimately，we hope to provide a new therapeutic target in the treatment of atheroscleross.

英文关键词： HDL;SR-BI;hematopoietic stem/progenitor cells;atherosclerosis;inflammation