Ablation of Plasma Prekallikrein Decreases Low-Density Lipoprotein Cholesterol by Stabilizing Low-Density Lipoprotein Receptor and Protects Against Atherosclerosis

可欣 PCSK9 医学 内科学 内分泌学 脂蛋白 家族性高胆固醇血症 脂蛋白(a) 前蛋白转化酶 低密度脂蛋白受体 胆固醇 载脂蛋白B 极低密度脂蛋白 高密度脂蛋白 低密度脂蛋白
作者
Jinkai Wang,Yan Li,Xiaolu Zhao,Yuanbin Liu,Jing Tan,Yu-ying Xing,Dilare Adi,Yongtao Wang,Zhen-Yan Fu,Yi-Tong Ma,Song-Mei Liu,Yong Liu,Yan Wang,Xiongjie Shi,Xiaoyi Lu,Bao-Liang Song,Jie Luo
出处
期刊:Circulation [Ovid Technologies (Wolters Kluwer)]
卷期号:145 (9): 675-687 被引量:4
标识
DOI:10.1161/circulationaha.121.056491
摘要

High blood cholesterol accelerates the progression of atherosclerosis, which is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis, which results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease.Low-density lipoprotein (LDL) receptor (LDLR) was used as bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK; encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han people was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo, we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice and knocked down Klkb1 using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and proprotein convertase subtilisin/kexin 9 inhibition also was evaluated. In addition, we applied the anti-PK neutralizing antibody that blocked the PK and LDLR interaction in mice. Mice lacking both PK and apolipoprotein e (Klkb1-/-Apoe-/-) were generated to assess the role of PK in atherosclerosis.PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of proprotein convertase subtilisin/kexin 9 with evolocumab further decreased plasma LDL cholesterol levels in Klkb1-deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed the progression of atherosclerosis in mice on Apoe-deficient background.PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol, and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat atherosclerotic cardiovascular disease.
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