Lp-PLA 2 (Lipoprotein-Associated Phospholipase A 2 ) Deficiency Lowers Cholesterol Levels and Protects Against Atherosclerosis in Rabbits

作者：Jiahuan Chen, Huanyu Zhang, Linquan Li, Xinwei Zhang, Dazhong Zhao, Lingyu Wang, Jiaqi Wang, Ping Yang, Huan Sun, Kun Liu, Weiwei Chen, Lin Li, Lin Feng, Zhanjun Li, Y. Eugene Chen, Jifeng Zhang, Daxin Pang, Hongsheng Ouyang, Yuquan He, Jianglin Fan, Xiaochun Tang · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2022 · DOI：10.1161/atvbaha.122.317898 · 被引用次数：15 · 研究领域：Lipoproteins and Cardiovascular Health、Vitamin K Research Studies、Cholesterol and Lipid Metabolism

Background: Elevated plasma Lp-PLA 2 (lipoprotein-associated phospholipase A 2 ) activity is closely associated with an increased risk of cardiovascular events. However, whether and how Lp-PLA 2 is directly involved in the pathogenesis of atherosclerosis is still unclear. To examine the hypothesis that Lp-PLA 2 could be a potential preventative target of atherosclerosis, we generated Lp-PLA 2 knockout rabbits and investigated the pathophysiological functions of Lp-PLA 2 . Methods: Lp-PLA 2 knockout rabbits were generated using CRISPR/Cas9 system to assess the role of Lp-PLA 2 in plasma lipids regulation and identify its underlying molecular mechanisms. Homozygous knockout rabbits along with wild-type rabbits were fed a cholesterol-rich diet for up to 14 weeks and their atherosclerotic lesions were compared. Moreover, the effects of Lp-PLA 2 deficiency on the key cellular behaviors in atherosclerosis were assessed in vitro. Results: When rabbits were fed a standard diet, Lp-PLA 2 deficiency led to a significant reduction in plasma lipids. The decreased protein levels of SREBP2 (sterol regulatory element-binding protein 2) and HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) in livers of homozygous knockout rabbits indicated that the cholesterol biosynthetic pathway was impaired with Lp-PLA 2 deficiency. In vitro experiments further demonstrated that intracellular Lp-PLA 2 efficiently enhanced SREBP2-related cholesterol biosynthesis signaling independently of INSIGs (ins...