Ablation of Plasma Prekallikrein Decreases LDL Cholesterol by Stabilizing LDL Receptor and Protects against Atherosclerosis.

Background: High blood cholesterol accelerates the progression of atherosclerosis that is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis that results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease (ASCVD). Methods: Low-density lipoprotein (LDL) receptor (LDLR) was used as the 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 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, as well as knocked Klkb1 down using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and PCSK9 inhibition was evaluated as well. We also applied the anti-PK neutralizing antibody that blocked PK and LDLR interaction to 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 PCSK9 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 down 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 ASCVD.