当前位置：
X-MOL 学术
›
Circulation
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Ablation of Plasma Prekallikrein Decreases Low-Density Lipoprotein Cholesterol by Stabilizing Low-Density Lipoprotein Receptor and Protects Against Atherosclerosis
Circulation ( IF 37.8 ) Pub Date : 2022-02-22 , DOI: 10.1161/circulationaha.121.056491 Jin-Kai Wang 1 , Yang Li 2 , Xiao-Lu Zhao 1 , Yuan-Bin Liu 1 , Jing Tan 1 , Yu-Ying Xing 1 , Dilare Adi 2 , Yong-Tao Wang 2 , Zhen-Yan Fu 2 , Yi-Tong Ma 2 , Song-Mei Liu 3 , Yong Liu 1 , Yan Wang 1 , Xiong-Jie Shi 1 , Xiao-Yi Lu 1 , Bao-Liang Song 1 , Jie Luo 1
Circulation ( IF 37.8 ) Pub Date : 2022-02-22 , DOI: 10.1161/circulationaha.121.056491 Jin-Kai Wang 1 , Yang Li 2 , Xiao-Lu Zhao 1 , Yuan-Bin Liu 1 , Jing Tan 1 , Yu-Ying Xing 1 , Dilare Adi 2 , Yong-Tao Wang 2 , Zhen-Yan Fu 2 , Yi-Tong Ma 2 , Song-Mei Liu 3 , Yong Liu 1 , Yan Wang 1 , Xiong-Jie Shi 1 , Xiao-Yi Lu 1 , Bao-Liang Song 1 , Jie Luo 1
Affiliation
Background: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.Methods: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.Results: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.Conclusions: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.
更新日期：2022-02-22
京公网安备 11010802027423号