Plasma prekallikrein levels are positively associated with circulating lipid levels and the metabolic syndrome in children

MacKenzie, James A.; Roosa, Kristen; Gump, Brooks B.; Dumas, Amy K.; Bendinskas, Kestutis

doi:10.1139/h10-039

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…The serum level of PK is positively correlated with low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) but not with high-density lipoprotein cholesterol (HDL-C) in young adult Han Chinese (aged 17–25 years). A previous study also demonstrated similar correlations in children aged 9–11 years [ 9 ]. This means that an increase in serum PK levels leads to increased lipid levels, thus leading to an increased occurrence of hyperlipidemia.…”

Section: Introductionsupporting

confidence: 75%

Circulating prekallikrein levels are correlated with lipid levels in the chinese population: a cross-sectional study

et al. 2023

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Background Recent evidence has revealed that circulating coagulation factor prekallikrein (PK), an important part of the kallikrein-kinin system, regulates cholesterol metabolism, but the association between serum PK and lipid levels is unclear. Methods This cross-sectional study included 256 subjects (aged from 1 month to 90 years) who underwent physical examinations at the First People’s Hospital of Huaihua, China. After overnight fasting, serum was collected for PK and lipid testing. Spearman correlation analysis and multivariable logistic regression analysis were used to analyze the association of PK level with lipid levels and the likelihood risk of hyperlipidemia. The possible threshold value of PK was calculated according to the receiver operating characteristic (ROC) curve. Results The median serum PK level was 280.9 µg/mL (IQR 168.0, 377.0), and this level changed with age but not sex. The serum PK level was positively correlated with the serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. A nonlinear relationship was observed between serum PK and high-density lipoprotein cholesterol (HDL-C) levels. The serum PK level was positively correlated with HDL-C when its level was lower than 240 µg/mL and negatively correlated with HDL-C when its level was higher than 240 µg/mL. The regression analysis demonstrated that an elevated serum PK level was significantly associated with the likelihood risk of hypercholesterolemia and hypertriglyceridemia. The ROC curve showed that the possible threshold values of serum PK for hypercholesterolemia and hypertriglyceridemia occurrences were 344.9 µg/mL and 305.7 µg/mL, respectively. Conclusions Elevated serum PK levels were significantly associated with the likelihood of hypercholesterolemia and hypertriglyceridemia, and the possible threshold values of PK levels were 344.9 µg/mL and 305.70 µg/mL, respectively, suggesting that higher PK levels may be a risk factor for cardiovascular diseases.

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Section: Introductionsupporting

confidence: 75%

Circulating prekallikrein levels are correlated with lipid levels in the chinese population: a cross-sectional study

et al. 2023

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“…Plasma PK level was also found to be positively correlated with circulating LDL-C in children. 39 Moreover, several KLKB1 variants have been reported to be associated with coronary artery disease. Suhre et al 40 reported that rs4253252 of KLKB1 had a weak association with coronary artery disease in the CARDIOGRAM study (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Zhao

et al. 2022

Circulation

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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.

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“…Plasma kallikrein levels were associated with the risk of CVD and stroke in men, and individuals who experienced an MI had higher levels of plasma kallikrein (21,22). Children with abnormal lipid profiles and metabolic syndrome had elevated plasma kallikrein levels that were associated with CVD risk factors (23). Furthermore, polymorphisms in plasma kallikrein (rs3733402) that results in reduced plasma kallikrein activity are associated with reduced CVD risk (24).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Plasma Kallikrein Levels and Their Association With the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

et al. 2020

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We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort of type 1 diabetes (T1D). Plasma kallikrein levels were measured longitudinally in 693 subjects at DCCT baseline (1983–1989), midpoint (1988–1991), and end (1993) and at EDIC years 4–6 (1997–1999), 8–10 (2001–2003), and 11–13 (2004–2006). Cox proportional hazards regression models assessed the association between plasma kallikrein levels and the risk of CVD. In unadjusted models, higher plasma kallikrein levels were associated with higher risk of any CVD during DCCT/EDIC (hazard ratio [HR] = 1.16 per 20 nmol/L higher levels of plasma kallikrein; P = 0.0177) as well as over the EDIC-only period (HR = 1.22; P = 0.0024). The association between plasma kallikrein levels and the risk of any CVD remained significant during the EDIC follow-up after adjustment for age and mean HbA1c (HR = 1.20; P = 0.0082) and in the fully adjusted model for other CVD risk factors (HR = 1.17; P = 0.0330). For MACE, higher plasma kallikrein levels were associated with higher risk in the unadjusted (HR = 1.25; P = 0.0145), minimally adjusted (HR = 1.23; P = 0.0417, and fully adjusted (HR = 1.27; P = 0.0328) models for EDIC only. These novel findings indicate that plasma kallikrein level associates with the risk of any CVD and MACE in T1D individuals.

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Plasma prekallikrein levels are positively associated with circulating lipid levels and the metabolic syndrome in children

Cited by 5 publications

References 38 publications

Circulating prekallikrein levels are correlated with lipid levels in the chinese population: a cross-sectional study

Circulating prekallikrein levels are correlated with lipid levels in the chinese population: a cross-sectional study

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

Longitudinal Plasma Kallikrein Levels and Their Association With the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

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