内皮细胞SR-BⅠ介导的氧化LDL转运途径及调节机制研究

Subendothelial oxLDL deposition is one of the key initial steps in AS plaque formation. In early period of AS, oxLDL in plasma can be endocytosed into or transported across endothelial cell in a caveolae-mediated way. However, the transport pathway and regulation mechanism of oxLDL in endothelial cells remain unclear. We found that compared to LDL, the amount of oxLDL transcytosis was decreased due to its degration after its transportion to lysosomes once endocytosed. It’s well known that the scavenger receptor SR-BI can distinguish oxLDL and LDL, but whether it is involved in the lysosomal transport pathway of oxLDL is still unknown. So we speculate that: SR-BⅠ in endothelial cells may mediate oxLDL endocytosis and intracellular trafficking signals, increase autophagy-related oxLDL transport to lysosomal, which indirectly affect the oxLDL transcytosis. In this study, we will observe the oxLDL transport process in different stages after silencing SR-BI in endothelial cells, analyze the role of SR-BI in each stage and explore its possible mechanisms;we will further exlpore the effect of SR-BI on endothelial cell transport and subendothelial deposition of oxLDL in vivo by utilizing SR-BI-/- mice. We hope to provide new ideas and theoretical basis for prevention and treatment of lipid deposition in early AS.

血管内皮下oxLDL沉积是AS斑块形成的关键起始步骤之一。在内皮层完整的AS早期，血浆中oxLDL可经小窝介导的方式被内皮细胞内吞、穿胞。但oxLDL在内皮细胞的转运途径及调节机制尚不清楚。我们发现，对比于LDL，oxLDL经内吞后可能被转运至溶酶体降解而间接减少穿胞。已知清道夫受体SR-BⅠ可区分性识别oxLDL和LDL，但其是否参与oxLDL溶酶体转运途径仍未知。综合文献和预实验结果，我们推测：内皮细胞SR-BⅠ可能介导oxLDL内吞及胞内运输信号，增加自噬相关的oxLDL定向溶酶体转运途径，从而间接影响oxLDL穿胞量。本项目拟先在内皮细胞靶向沉默SR-BⅠ，分阶段观察oxLDL转运过程，分析SR-BⅠ在各阶段的参与性并探讨其可能机制；再利用SR-BⅠ-/-小鼠，在组织和动物水平探讨SR-BⅠ对oxLDL的内皮细胞转运及内皮下沉积的影响，为AS早期脂质沉积的防治提供新的思路和依据。

血浆中oxLDL作用于主动脉内皮细胞并转运到内皮下沉积的过程是AS斑块形成的关键起始步骤之一。我们前期研究发现，对比于LDL，oxLDL经内吞后可能被转运至溶酶体降解而间接减少穿胞。已知清道夫受体SR-BⅠ可区分性识别oxLDL和LDL，但其是否参与oxLDL溶酶体转运途径仍未知。因此，本课题对比了LDL和oxLDL在内皮细胞的转运过程和对内皮细胞功能状态的影响，利用SR-BⅠ低表达的内皮细胞，探讨SR-BⅠ对oxLDL转运过程的参与性并分析SR-BⅠ对内皮细胞自噬信号通路的调节作用。另外，利用apoE-/-小鼠动脉粥样硬化模型，检测到作用于自噬和氧还信号的药物对动脉粥样硬化斑块形成的调节作用及其对oxLDL经内皮细胞转运的影响，为AS早期脂质沉积的防治提供新的思路和依据。