动脉粥样硬化中脂噬功能异常在血管平滑肌细胞泡沫样变中的作用和机制研究

Vascular smooth muscle cell (VSMC) is the major source of foam cell in advanced atherosclerosis lesions. However, the precise underlying mechanisms are remain unclear. Studies suggested that lipophagy was a selective form of autophagy. This selectivity allows autophagy to specifically break down lipid droplets’ lipid stores. And the breakdown of neutral lipid was mainly through lipophagy pathway. Our previous study of this project found that VSMC loaded with oxLDL showed impaired lipophagy , which leading to lipid droplets accumulation in VSMC. Sterol regulatory-element binding proteins-1 (SREBP-1) was one of the most important transcription factors of lipid metabolism. SREBP cleavage activating protein (SCAP ) was a regulatory protein required for the proteolytic maturation of SREBP-1. A previous study reported that the activation of SREBP-1 promoted cholesterol ester accumulation in VSMC. Herein, We speculated that the persistent and excess lipid stimulation inside AS plaque impaires the VSMC lipophagy through activating of SREBP-1/SCAP signaling pathway, and promotes lipid droplets accumulation in VSMC, which enventually leads to VSMC-derived foam cells formation. Accordingly, we plan to: 1) detect the VSMC lipophagy in high-fat-diet-induced AS plaque and in oxLDL-induced VSMC foam cells, respectively. 2) detect the effect of lipophagy dysfunction on VSMC foam cell formation after inhibition the lipophagic flux. 3) investigate the possible role of SREBP-1/SCAP signaling pathway in lipid-induced lipophagy dyfunction in the process of VSMC foam cell formation. The results of this project will provide further insight into the mechanisms of VSMC foam cell formation and help to find novel therapeutic target for the prevention and treatment of atherosclerosis.

血管平滑肌细胞（VSMC）是动脉粥样硬化（AS）晚期病变中泡沫细胞的主要来源，但其形成的具体机制仍不明确。脂噬是中性脂质在细胞内的主要代谢途径。研究发现，在AS病变中，持续高浓度脂质刺激导致脂噬功能降低。我们前期的实验证实，大剂量氧化型低密度脂蛋白（oxLDL）刺激可抑制VSMC脂噬，促进VSMC内脂滴堆积，诱导平滑肌源性泡沫细胞形成，其机制可能与脂质代谢转录因子SREBP-1及其剪切活化蛋白SCAP活化有关。据此，本项目拟建立高脂诱导的AS模型和oxLDL诱导的VSMC泡沫细胞模型，明确AS病变中VSMC脂噬情况。调控VSMC内脂噬小体形成，调控脂噬流及调控SREBP-1/SCAP活性，明确脂噬参与调节VSMC内脂滴堆积，并积极探讨其发生的具体分子机制，为寻找防治AS新的治疗靶点提供理论依据。

血管平滑肌细胞（VSMC）是动脉粥样硬化（AS）晚期病变中泡沫细胞的主要来源，但其形成的具体机制仍不明确，既往研究证实脂噬是中性脂质在细胞内的主要代谢途径。我们的研究发现，随着氧化型低密度脂蛋白（oxLDL）刺激培养时间的增加，VSMC内脂滴的聚集逐渐增多，但脂噬小体的形成逐渐减少，同时自噬相关分子Atg5、LC3B蛋白表达较对照组下降。siRNA抑制Atg5基因表达后，脂噬小体形成较oxLDL刺激组明显减少，而脂滴聚集明显增多。提示脂噬功能障碍参与VSMC源性泡沫细胞形成，为寻找防治AS新的治疗靶点提供理论依据。