Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

scholarly journals Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of dyslipidemia

2021 ◽  
pp. 12-18
Author(s):  
A. A. Shikaleva ◽  
M. L. Maximov ◽  
N. M. Kiseleva
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Lipid Lowering ◽  
Substantial Contribution ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Levels ◽  
Density Lipoprotein Receptor

Dyslipidemia makes a substantial contribution to the mortality as one of the leading pathogenetic factors for cardiovascular diseases. The nature and degree of the effect on the blood lipid spectrum may vary in the lipid-lowering drugs from different groups. Recently, a new class of PCSK9 inhibitors has been developed, which activity is associated with a protein involved in the low-density lipoprotein receptor control. In clinical practice, this group is represented by monoclonal antibody drugs evolocumab and alirocumab. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are promising drugs to be used in the combination lipid-lowering therapy, which, given the results of clinical trials, can be recommended at this point on a third-priority basis after statins and ezetimibe. However, it is vital to indicate that these drugs have a sufficient safety profile, which makes it possible to prescribe these drugs in a triple combination adding it to the two first-line drugs regimen which patients had been given before. It is obvious that further study of PCSK9 will expand the range of their use for the treatment of familial hypercholesterolemia up to indications in cases where statins are limited and a more pronounced lipid-lowering effect is required to achieve target cholesterol levels.

scholarly journals Proprotein convertase subtilisin/kexin type 9: A new target molecule for gene therapy

2012 ◽  
Vol 17 (2) ◽  
Author(s):  
Anna Banaszewska ◽  
Michal Piechota ◽  
Robert Plewa
Keyword(s):  
Antisense Oligonucleotides ◽  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Therapeutic Strategies ◽  
Lipid Lowering ◽  
Small Interfering Rnas ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Novel Target

AbstractProprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel target for controlling plasma levels of low-density lipoprotein cholesterol (LDL-C) and decreasing the risk of cardiovascular diseases. At present it is clear that the major classes of commonly prescribed lipid-lowering medications increase serum PCSK9 levels and fail to protect a significant percentage of patients from cardiovascular events. Therefore development of new LDL-C lowering medications that either do not increase circulating PCSK9 levels or work through inhibition of PCSK9 expression and protease activity is a highly desirable approach to overcome hypercholesterolemia. Since there are several agents which are being evaluated in human preclinical and clinical trials, this review summarizes current therapeutic strategies targeting PCSK9, including specific antibodies, antisense oligonucleotides, small interfering RNAs (siRNAs) and other small-molecule inhibitors.

Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis

2020 ◽  
Vol 27 (31) ◽  
pp. 5159-5174 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Biological Functions ◽  
Pharmacological Management ◽  
Vascular Growth ◽  
Promising Target ◽  
And Function ◽  
Systematic Appraisal

Background:Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism.Method:A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis.Results:Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects.Conclusion:ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions.

Efficacy and Safety of Evolocumab in Reducing Low Density Lipoprotein Cholesterol Levels in Chinese Patients with Non-ST-segment Elevation Acute Coronary Syndrome

2020 ◽  
Vol 18 ◽  
Author(s):  
Xiaohan Xu ◽  
Meng Chai ◽  
Yujing Cheng ◽  
Pingan Peng ◽  
Xiaoli Liu ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Chinese Patients ◽  
Lipid Lowering ◽  
Control Group ◽  
Lipid Lowering Therapy ◽  
St Segment Elevation ◽  
Coronary Syndrome ◽  
St Segment

Aims: To explore early intensive lipid-lowering therapy in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels can reduce cardiovascular morbidity and mortality in patients with atherosclerotic cardiovascular disease. Due to many reasons, the need for early intensive lipid-lowering therapy is far from being met in Chinese NSTE-ACS patients at high-risk of recurrent ischaemic events. Objective: To evaluate the feasibility, safety and efficacy of starting evolocumab in hospital to lower LDL-C levels in Chinese patients with NSTE-ACS. Methods: In this prospective cohort study initiated by researchers, 334 consecutive patients with NSTE-ACS who had sub-standard LDL-C levels (LDL-C ≥2.3 mmol/L after regular oral statin treatment for at least 4 weeks; or LDL-C ≥3.2 mmol/L without regular oral statin treatment) were included. Patients who agreed to treatment with evolocumab (140 mg subcutaneously every 2 weeks, initiated in hospital and used for 12 weeks after discharge) were enrolled in the evolocumab group (n=96) and others in the control group (n=238). All enrolled patients received regular statin treatment (atorvastatin 20 mg/day or rosuvastatin 10 mg/day; doses unchanged throughout the study).The primary endpoint was the change in LDL-C levels from baseline to week 12. Results: Most patients (67.1%) had not received regular statin treatment before. In the evolocumab group, LDL-C levels decreased significantly at week 4 and remained stable at week 8 and 12 (all p<0.001). At week 12, the LDL-C percentage change from baseline in the evolocumab group was -79.2±12.7% (from an average of 3.7 to 0.7 mmol/L), while in the control group it was -37.4±15.4% (from an average of 3.3 to 2.0 mmol/L). The mean difference between these 2 groups was -41.8% (95% CI -45.0 to -38.5%; p<0.001). At week 12, the proportions of patients with LDL-C levels <1.8 mmol/L and 1.4 mmol/L in the evolocumab group were significantly higher than in the control group (96.8 vs 36.1%; 90.6 vs 7.1%; both p<0.001). The incidence of adverse events and cardiovascular events was similar in both groups. Conclusions: In this prospective cohort study we evaluated the early initiation of evolocumab in NSTE-ACS patients in China. Evolocumab combined with statins significantly lowered LDL-C levels and increased the probability of achieving recommended LDL-C levels, with satisfactory safety and well tolerance.

Abstract P560: Delipid Extracorporeal Lipoprotein Filter System: A New Lipid-Lowering Therapy for Acute Ischemic Stroke Patients

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Yuqiong Jiao ◽  
Ting Ye ◽  
Xiang Han
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Plasma Lipids ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Adsorption System ◽  
Stroke Patients ◽  
Safety Parameters

Objectives: The purpose of this study was to illustrate a new low-density lipoprotein cholesterol (LDL-C) adsorption system, Delipid Extracorporeal Lipoprotein filter from Plasma (DELP) system, and evaluate its safety and efficacy in acute ischemic stroke patients. Methods: This is an observational study of 22 acute ischemic stroke patients who underwent DELP treatment from March to August 2019. The DELP system was composed of a plasma filter JX-DELP, a COM.TEC cell separator and Tubing P1R Plasma Treatment Set. Clinical data and laboratory results including plasma lipids and some safety parameters before and after the apheresis were collected and analyzed. Results: The present study included 22 patients (15 males, 7 females, 59.95±13.71 years). The mean LDL-C was significantly reduced from 3.36±0.64 mmol/L to 2.30±0.53 mmol/L (31.5%, p <0.001, n=22) during a single DELP treatment, and from 3.59±0.48 mmol/L to 1.85±0.50 mmol/L (48.2%, p <0.001, n=13) after two apheresis, respectively. No clinically relevant changes were observed in hematologic safety parameters during DELP treatments. Conclusions: We concluded that the new LDL-C adsorption system is a promising method for timely and controllable LDL-C administration in acute ischemic stroke patients in view of its high efficacy, simple operation, and safety.

scholarly journals U-Shaped Relationship of Low-Density Lipoprotein Cholesterol With Risk of Severe COVID-19 From a Multicenter Pooled Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiao Gong ◽  
Yaqiong Chen ◽  
Yusheng Jie ◽  
Mingkai Tan ◽  
Zhaofang Jiang ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Odds Ratios ◽  
Lowering Therapy ◽  
Severe Group

Low-density lipoprotein cholesterol (LDL-C) is a well-known risk factor for coronary heart disease but protects against infection and sepsis. We aimed to disclose the exact association between LDL-C and severe 2019 novel coronavirus disease (COVID-19). Baseline data were retrospectively collected for 601 non-severe COVID-19 patients from two centers in Guangzhou and one center in Shenzhen, and patients on admission were medically observed for at least 15 days to determine the final outcome, including the non-severe group (n = 460) and the severe group (severe and critical cases) (n = 141). Among 601 cases, 76 (12.65%) received lipid-lowering therapy; the proportion of patients taking lipid-lowering drugs in the severe group was higher than that in the non-severe group (22.7 vs. 9.6%). We found a U-shaped association between LDL-C level and risk of severe COVID-19 using restricted cubic splines. Using univariate logistic regression analysis, odds ratios for severe COVID-19 for patients with LDL-C ≤1.6 mmol/L (61.9 mg/dL) and above 3.4 mmol/L (131.4 mg/dL) were 2.29 (95% confidence interval 1.12–4.68; p = 0.023) and 2.02 (1.04–3.94; p = 0.039), respectively, compared to those with LDL-C of 2.81–3.40 mmol/L (108.6–131.4 mg/dL); following multifactorial adjustment, odds ratios were 2.61 (1.07–6.37; p = 0.035) and 2.36 (1.09–5.14; p = 0.030). Similar results were yielded using 0.3 and 0.5 mmol/L categories of LDL-C and sensitivity analyses. Both low and high LDL-C levels were significantly associated with higher risk of severe COVID-19. Although our findings do not necessarily imply causality, they suggest that clinicians should pay more attention to lipid-lowering therapy in COVID-19 patients to improve clinical prognosis.

Comparison of LDL-C calculation by friedewald and martin/hopkins methods in 12,243 adults from the United States of America

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Penson ◽  
S.S Martin ◽  
N.C Henney ◽  
M Banach
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Threshold Value ◽  
The United States ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Strongly Correlated ◽  
Low Density Lipoprotein Cholesterol

Abstract Background Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for cardiovascular disease (CVD), and a target for lipid-lowering therapy. LDL-C is typically not measured directly but is estimated using the Friedewald formula, which assumes a fixed factor for the ratio of triglycerides (TG) to very low-density lipoprotein cholesterol (VLDL-C). However this assumption is sometimes not valid. The Martin/Hopkins (M/H) formula estimates LDL-C using an adjustable factor for the TG:VLDL-C ratio and is expected to improve upon Friedewald when predicting measured LDL-C, and apolipoprotein B (ApoB), one molecule of which is associated with each LDL particle. Purpose We compared values of LDL-C calculated by the Friedewald and M/H methods with respect to their correlation with non-high density lipoprotein cholesterol (non-HDL-C) and ApoB, and their classification of individuals based upon attainment of the threshold value of 70 mg/dl (1.8 mmol/l) of LDL-C. This cut-point is a treatment target for individuals at high risk of CVD in the 2019 ESC guidelines for lipid modification, and a threshold for initiating statin therapy in the 2019 ACC/AHA guidelines. Methods In this analysis we included participants in the National Health and Nutrition Examination Survey (NHANES) from 2005–2016, age ≥18, &lt;80 years who had measurements for total cholesterol (TC), TG and HDL-C. LDL-C was calculated using Friedewald and M/H. We correlated LDL-C (calculated using the two methods) with non-HDL-C and ApoB. We identified individuals with LDL-C &lt;70 mg/dl using both methods. When LDL-C (Friedewald) was &lt;70, but LDL-C (M/H) was &gt;70, we classified these participants as discordant. Statistical analyses were performed in IBM SPSS for Windows v26. Results 12,243 individuals were included. 51.8% were female, mean (±SD) age was 45.5±17.4, 15.3% were treated with statins, ApoB was available for 2179 participants. Mean lipid concentrations (mg/dl) were: TC: 191.5±41.0, TG: 120.0±67.0, HDL-C: 54.1±15.7, LDL-C (Friedewald): 113.3±35.4; LDL-C (M/H): 114.9±35.2. In the whole population, LDL-C (M/H) was more strongly correlated than LDL-C (Friedewald) with ApoB (r=0.935 v 0.894) and non-HDL-C (r=0.981 v 0.944). In statin-treated participants, LDL-C (M/H) was also more strongly correlated with ApoB (r=0.951 v 0.914) and non-HDL-C (r=0.979 v 0.928). 1139 participants had LDL-C (Friedewald) &lt;70 mg/dl. Of these, 206 individuals (18.1%) were discordant, having LDL-C (M/H) &gt;70 mg/dl. Amongst statin-treated patients, 22.9% were discordant. Only 5.5% of individuals with LDL-C (M/H) &lt;70 mg/dl showed reverse discordance (LDL-C (Friedewald) &gt;70 mg/dl). Conclusions The M/H method of calculating LDL-C correlates more strongly with non-HDL-C and ApoB than Friedewald. Importantly the discordant results confirm previous observations that Friedewald underestimates LDL-C at low concentrations. This may result in under-use of lipid-lowering therapies. Funding Acknowledgement Type of funding source: None

P829The impact of APOC3 and APOE gene polymorphisms on response to statin therapy in acute myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Teterina ◽  
A Geraskin ◽  
P Potapov ◽  
L Babaeva ◽  
A Pisaryuk ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Statin Therapy ◽  
Gene Polymorphisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Genetic Studies ◽  
Apoc3 Gene ◽  
Pronounced Reduction

Abstract Background and aim Many genetic studies have been reported about the association between APOE, APOC3 gene polymorphisms and response to statin therapy in myocardial infarction, but results remain controversial. The aim of this study was to investigate the association between SNP rs7412 (APOE), rs2854117 (APOC3), rs2854116 (APOC3) and lipid-lowering effect of atorvastatin and rosuvastatin in patients with myocardial infarction. Methods Polymorphism of genes APOE (rs7412), APOC3 (rs2854117 and rs2854116) was determened. Lipid profile was determined on admission and after 1 year of treatment. Results 78 patients with myocardial infarction treated with maximal tolerated dose of atorvastatin or rosuvastatin were included. More pronounced reduction of lipid levels was associated with of T allele of rs7412 (APOE), p<0,05. ANOVA demonstrated greater low-density lipoprotein and total cholesterol decrease in patients with combination of genes CT/TT (rs7412, APOE) and CC (rs2854117, APOC3) genotypes, CT/TT (rs7412, APOE) and CT (rs2854116, APOC3) genotypes. Conclusion The genetic variants of APOC3 and APOE are useful markers and can be use to predict response to lipid-lowering therapy with statin in myocardial infarction.

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