自噬对高脂膳食诱导的血管内皮细胞损伤的保护作用及分子机制研究

Cardiovascular disease (CVD) is the first killer for human life. Arteriosclerosis (AS) is well-regarded as an essential risk reason for CVD. The pathological mechanisms of AS are complex and still not clear so far. The progressive increase of AS incidence rate in our country is closely with the percentage augmentation of the energy in the diet. Recent studies have reported that high-fat diet-induced injury in vascular endothelium was a pivotal pathological basis in the progress of AS. Autophagy is a highly conservative biological progress, which is existed in eucaryotic cells. Recently, researches on the relationship between autophagy and lots of diseases has become the hot point in bioscience with the more understanding on the regulation of autophagy. However, these studies were only in the beginning stage, and lots of scientific problems need to be discovered. Dose autophagy play a protective role on high-fat diet-induced injury in vascular endothelium and also AS plaque formation is still unclear to us. Our previous study observed that activating autophagy markedly inhibited inflammatory cytokines- or FFA-induced dysfunction, injury, and even apoptosis in vascular endothelium cells. Therefore, the present item aimed to investigate the effect of autophagy on high-fat diet-induced injury in vascular endothelium tissue and the development of AS. Futhermore, molecular biology methods are employed to clarify its potential mechanisms via combining in vivo and in vitro experiments. This preject will provide favourable basis for the prevention and cure in the vascular endothelium injury and AS. The successful execution of this project has substaintial practical importance and research value on the prevention and cure of AS and CVD.

心血管疾病（CVD）是威胁人类生命的头号杀手。动脉粥样硬化（AS）是公认的引起CVD的主要原因，且发病机制复杂。我国居民膳食能量的增加与其发病率逐年升高密切相关。研究表明，高脂膳食模式诱导的血管内皮损伤是AS发生的重要病理基础。自噬是广泛存在于真核细胞中、高度保守的生物学过程。随着自噬调控机制的逐步完善，其与CVD关系的研究已成为生命科学的研究热点。然而该研究尚处于起始阶段，许多科学问题有待剖析。其中，自噬能否保护高脂膳食诱导的血管内皮损伤及AS的发生尚不明确。我们前期研究表明激活自噬可有效抑制炎性因子或游离脂肪酸诱导的内皮细胞功能损伤甚至凋亡。因此，本项目将就自噬对高脂膳食诱导的血管内皮细胞损伤及AS发生的保护作用进行研究，并通过体内外相结合的模式阐明其潜在的分子机制，为改善或防治我国居民AS发生提供新思路、新靶点。项目的顺利实施对防治AS乃至CVD的发生具有重要的现实意义和研究价值。

心血管疾病是威胁人类健康与生命的最常见疾病，其发病率和死亡率居世界首位，同时也是导致我国居民死亡的最主要疾病。伴随居民生活水平的提高，高能量膳食已成为诱导心血管疾病高发的重要因素。血管内皮组织是血管系统的重要屏障，其发生损伤或功能紊乱是导致心血管疾病的重要甚至起始原因。.本项目结合当今生命科学的热点领域--自噬，并将自噬干预应用到高脂膳食诱导的血管内皮细胞损伤及功能紊乱的研究中，通过体内外实验方法相结合的方式，应用分子生物学技术手段，探索保护血管内皮细胞损伤的新途径及新的干预靶点，为新型药物的研发提供科学依据。.目前已按计划完成全部研究内容，共发表SCI标注论文5篇，发表会议论文4篇，获得省部级一等奖一项，培养博士1名，硕士研究生1名，目前在读博士研究生1名，参加国际学术会议2次。具体研究结果如下：.1..激活自噬能够显著改善高脂膳食诱导引起的血管内皮细胞粘附因子的激活，而抑制自噬显著加重了高脂膳食诱导的血管内皮细胞粘附因子的表达。.2..自噬通过调控p38介导的NFκB信号通路改善高脂等因素诱导血管内皮细胞粘附因子的激活.3..高脂膳食能够诱导显著的血管内皮细胞凋亡损伤，而激活自噬显著抑制高脂诱导引起的血管内皮细胞凋亡，而抑制自噬显著加重高脂膳食诱导的血管内皮细胞凋亡。.4..激活自噬显著改善饱和游离脂肪酸诱导的线粒体膜电位降低、抑制饱和游离脂肪酸诱导的内质网应激、改善饱和游离脂肪酸诱导的ERK1/2磷酸化保护血管内皮细胞的损伤。.上述研究结果表明，自噬干预可有效改善高能量膳食导致的血管内皮损伤及功能改变，针对自噬开展相关药物或功能产品研发对改善血管内皮功能具有重要现实意义。