Plasma Proprotein Convertase Subtilisin/kexin Type 9 Research Articles

Effects of antiretroviral therapy on lipid and immunovirological profile: Focus on proprotein convertase subtilisin/kexin 9

Aim: Lipid profile is generally deranged in antiretroviral (ART)-naive HIV+ patients due to HIV infection severity and immunodeficiency state. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol metabolism, is induced in some inflammatory states with a trend toward an increase in plasma levels in HIV untreated/treated patients compared to healthy controls. Whether plasma PCSK9 levels may decrease after ART initiation is not established. We measured plasma lipid and PCSK9 levels in ART-naive HIV+ patients and investigated the impact of ART initiation on these parameters.

Low-density lipoprotein (LDL)-dependent uptake of Gram-positive lipoteichoic acid and Gram-negative lipopolysaccharide occurs through LDL receptor

Lipoteichoic acid (LTA) and lipopolysaccharide (LPS) are bacterial lipids that stimulate pro-inflammatory cytokine production, thereby exacerbating sepsis pathophysiology. Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates uptake of cholesterol by downregulating hepatic lipoprotein receptors, including low-density lipoprotein (LDL) receptor (LDLR) and possibly LDLR-related protein-1 (LRP1). PCSK9 also negatively regulates Gram-negative LPS uptake by hepatocytes, however this mechanism is not completely characterized and mechanisms of Gram-positive LTA uptake are unknown. Therefore, our objective was to elucidate the mechanisms through which PCSK9 regulates uptake of LTA and LPS by investigating the roles of lipoproteins and lipoprotein receptors. Here we show that plasma PCSK9 concentrations increase transiently over time in septic and non-septic critically ill patients, with highly similar profiles over 14 days. Using flow cytometry, we demonstrate that PCSK9 negatively regulates LDLR-mediated uptake of LTA and LPS by HepG2 hepatocytes through an LDL-dependent mechanism, whereas LRP1 and high-density lipoprotein do not contribute to this uptake pathway. Bacterial lipid uptake by hepatocytes was not associated with cytokine production or hepatocellular injury. In conclusion, our study characterizes an LDL-dependent and LDLR-mediated bacterial lipid uptake pathway regulated by PCSK9, and provides evidence in support of PCSK9 inhibition as a potential therapeutic strategy for sepsis.

Association between plasma levels of PCSK9 and the presence of coronary artery disease in Japanese.

The ability of pro-protein convertase subtilisin/kexin type 9 (PCSK9) levels to predict the presence or severity of coronary artery disease (CAD) remains controversial. The purpose of this study was to investigate these associations. We enrolled 393 patients who were clinically suspected to have CAD or who had at least one cardiac risk factor and underwent multidetector-row computed tomography coronary angiography. The presence of CAD (≥50% coronary stenosis), the number of significantly stenosed coronary vessels, and plasma levels of PCSK9 by ELISA were analyzed. Plasma PCSK9 levels (log-transformed data) were significantly associated with the presence of CAD. Next, we divided the patients into two groups (non-statin and statin groups) according to statin treatment. PCSK9 levels in the non-statin group were significantly lower than those in the statin group. There were no significant differences in PCSK9 levels between the absence and presence of CAD in the statin group. However, in the non-statin group, PCSK9 levels in patients with CAD were significantly higher than those in patients without CAD. PCSK9 levels, in addition to age, gender, BMI, DM and HDL-C, were independently associated with the presence of CAD by a multivariable analysis. In conclusion, our results demonstrated that plasma PCSK9 levels may be a marker for evaluating the presence of CAD.

Analysis of the Association between PCSK9 Levels and Plasma Lipid Levels in Cameroonians with Type 2 Diabetes

Studies have shown that intensive LDL-lowering therapy results in a significant reduction in cardiovascular disease (CVD) risk and improved outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL cholesterol (LDL-C) and an independent CVD risk marker. PCSK9 has additionally been related to CRP which is also a CVD risk marker. The emerging importance of the inhibition of PCSK9 for the treatment of hypercholesterolemia warrants investigations in different populations. This is the first study evaluating the association between PCSK9 and plasma lipid levels in Sub-Saharan Africa. A Cross sectional analysis was conducted at a major hospital in Yaound9, Cameroon in a cohort of 82 participants (53% females) with median age of 51[42-58] years. There were 28 non-obese type 2 diabetes (T2D) patients with median known duration of diabetes of 3.08[1.06-6.50] years, matched for age and sex to 28 obese nondiabetic and 26 lean nondiabetic subjects. Serum PCSK9 levels were measured using sandwich ELISA method. PCSK9 and hs-CRP levels were significantly higher in obese and T2D subjects relative to the lean controls (p<0.001 and p =0.0respectively). BMI was an independent predictor for PCSK9 and hs-CRP levels and this association remained after adjustment for potential confounders. Lean female subjects had significantly higher PCSK9 levels than males (p=0.004) and positive correlation of PCSK9 with LDL-C and total cholesterol (r=0.4, p=0.048 and r=0.5, p=0.039 respectively). An association was not found between PCSK9 and plasma lipid levels in obese and type 2 diabetes subjects nor was it found between PCSK9 and hs-CRP. Obese and type 2 diabetes subjects have higher PCSK9 and hs-CRP levels when compared to lean controls, suggesting that these metabolic states potentially impact PCSK9 levels in Cameroonian patients. Disclosure C.B.M. Mba: None. W.F. Mbacham: None. E. Sobngwi: None. J. Mbanya: Advisory Panel; Self; GlaxoSmithKline plc.. Speaker's Bureau; Self; Novo Nordisk A/S, Sanofi, Servier.

Association between plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipids with rs7903146 polymorphisms of the TCF7L2 gene in diabetic patients

The rs7903146 polymorphism of TCF7L2 gene is known as the strongest genetic risk factor for type 2 diabetes mellitus (T2DM). The polymorphism is in association with clinical profile of T2DM patients. PCSK9 is a serine protease that promotes LDLR degradation and regulates circulating levels of lipids. The association of this polymorphism with PCSK9 and metabolic profile of diabetic and healthy subjects was investigated. This cross-sectional study was performed on 132 T2DM patients and the same number of healthy subjects. All the participants were genotyped for the rs7903146 single nucleotide polymorphism by the PCR-RFLP method. Metabolic profile including plasma levels of PCSK9, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol, HDL cholesterol, fasting plasma glucose, and HBA1C was measured. PCSK9, total cholesterol, and LDL-C levels were lower in the diabetic patients as compared to the healthy subjects. There were also direct and significant associations between PCSK9 and TG, TC, LDL-C, and non HDL-C in the subjects. Values of plasma glucose, HbA1c, PCSK9, TC, and LDL-C were higher in patients with TT genotype, but the differences were not statistically significant for all. A positive Spearman correlation was found between PCSK9 levels and the genotypes in all the participants. The results confirm the association of rs7903146 in the TCF7L2 gene with metabolic parameters and PCSK9. The T allele was associated with higher lipid and PCSK9 levels.

Abstract 629: The (Pro)renin Receptor Regulates Scavenger Receptor CD36 Protein Degradation and Functions

Background: Accumulation of oxidized lipids in monocyte-derived macrophages results in foam cell formation and induces chronic inflammation in the vascular wall, thus contributing to the onset and progression of atherosclerosis. Scavenger receptor CD36 is the most important clearance receptor for ox-LDL, and has been implicated in triggering inflammatory responses in macrophages by ox-LDL. Genetically deleting CD36 reduced foam cell formation and lesion size in ApoE -/- mice. Additionally, circulating macrophages isolated from patients that are deficient of CD36 show much less ox-LDL uptake and accumulation than those from normal subjects. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a regulator of CD36 protein degradation. Interestingly, we found that inhibiting the hepatic (pro)renin receptor [(P)RR] dramatically increased plasma PCSK9 levels in C57BL/6J mice. Thus, we wondered if the (P)RR could regulate CD36 protein degradation and functions by increasing PCSK9 levels. Methods and Results: We inhibited hepatic (P)RR expression in PCSK9 -/- mice and wildtype mice, using GalNAc-modified anti-sense oligos targeting the (P)RR. Hepatic (P)RR inhibition reduced hepatic CD36 protein abundance by ~40% in WT mice, without affecting CD36 transcriptional levels. Unexpectedly, inhibiting hepatic (P)RR in PCSK9 -/- mice showed a similar reduction in hepatic CD36 protein abundance, suggesting that such reduction in CD36 is unlikely to be mediated by increased plasma PCSK9 levels. To clarify this, we exogenously expressed CD36 in HEK293T cells and studied whether silencing the (P)RR could directly affect CD36 protein abundance. Indeed, silencing the (P)RR reduced exogenously expressed CD36 by almost 50%, confirming that the (P)RR directly controls CD36 degradation. Functional studies revealed that inhibiting/deleting the (P)RR attenuated fatty acid uptake in differentiated 3T3-L1 adipocytes, and ox-LDL uptake in circulating mouse macrophages in a CD36-dependent manner. Conclusion: The (P)RR acts as a post-transcriptional regulator of CD36, and this occurs in a PCSK9-independent manner. Macrophagic (P)RR may play a role in the development of atherosclerosis by interacting with CD36.

Correction: Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain

[This corrects the article DOI: 10.1371/journal.pbio.2001882.].

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol-lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms. To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels. PCSK9 forms were measured in plasma: (1) in 20 patients before and 6months after bariatric surgery and (2) in 132 patients before and 12months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry. Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P<.05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P<.001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P<.05). These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.

Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels.

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.

Plasma proprotein convertase subtilisin/Kexin type 9 (PCSK9) is associated with Lp(a) in non-CAD type 2 diabetic patients

Type 2 diabetes mellitus (T2DM) is associated with elevated plasma apolipoprotein B, Lp(a), triglycerides and reduced HDL-C. The present study was conducted to investigate whether plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of LDL-receptor (LDLr) expression in hepatocytes, was associated with diabetic dyslipidemia. We developed a sandwich ELISA using recombinant human PCSK9 protein and a polyclonal antibody pre-coated onto a microplate specific directed against human PCSK9. We measured circulating PCSK9 concentrations in a cohort of patients with T2DM ( n = 50) compared to an age- and sex-matched control group ( n = 50). Plasma apolipoprotein B, Lp(a) triglycerides, LDL-C, HDL-C and LDL-r were measured in both groups. Plasma PCSK9 levels were significantly elevated in T2DM compared to controls (44.61 ± 14.44 and 33.22 ± 11.79 ng/mL respectively, P < 0.0001). However, LDL-r levels did not differ between the two groups. No significant correlation of PCSK9 with lipid parameters was found. Remarkably PCSK9 was positively correlated with Lp(a) in whole population ( r = +0.254, P < 0.0138) and T2DM group ( r = +0287, P = 0.0474) but not in controls. Lp(a) levels has been proposed as a contributing factor to the accelerated development of macrovascular complications in T2DM and the synergic effect with PCSK9 may explain the enhanced atherogenicity in type 2 diabetic patients.

Relationship between Plasma Proprotein Convertase Subtilisin/Kexin Type 9 and Estimated Glomerular Filtration Rate in the General Chinese Population

Background: Elevated levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been reported to be related to dyslipidemia, including patients with kidney dysfunction. However, its association with estimated glomerular filtration rate (eGFR) in individuals with normal serum creatinine (SCr) has not been determined. Methods: A total of 2,089 subjects with normal SCr and without lipid-lowering treatment were consecutively enrolled in this study. Plasma PCSK9 levels were measured by ELISA kit and eGFR was evaluated by the Chronic Kidney Disease Epidemiology Collaboration equation. Subjects were divided into a normal eGFR group (n = 1,205, ≥90 mL/min/1.73 m²) and a decreased eGFR group (n = 884, < 90 mL/min/1.73 m²). Baseline characteristics and laboratory findings were compared between the two groups. Spearman’s correlation and linear regression were performed to determine the association between PCSK9 and eGFR. Results: No significant difference in PCSK9 levels was found between the normal eGFR group and the decreased eGFR group (236.84 ± 67.87 vs. 239.98 ± 68.72 ng/mL, p = 0.303). In Spearman’s correlation and multivariable linear regression analysis, no association of PCSK9 levels with eGFR was detected in the total cohort (r = –0.039, p = 0.079; adjusted β = –0.013, p = 0.630). This result remained the same in the subgroups of normal eGFR (r = –0.038, p = 0.190; adjusted β = –0.031, p = 0.367) and decreased eGFR (r = –0.054, p = 0.109; adjusted β = –0.034, p = 0.319). Conclusion: In this single-center study with moderate sample size, the data showed no relationship of PCSK9 levels with normal or decreased eGFR in untreated patients with normal SCr, suggesting that further studies may be needed to understand the relationship between PCSK9 and lipid disorder in different stage of kidney dysfunction.

Rosuvastatin Reduces Aortic Sinus and Coronary Artery Atherosclerosis in SR-B1 (Scavenger Receptor Class B Type 1)/ApoE (Apolipoprotein E) Double Knockout Mice Independently of Plasma Cholesterol Lowering.

Rosuvastatin has been widely used in the primary and secondary prevention of coronary heart disease. However, its antiatherosclerotic properties have not been tested in a mouse model that could mimic human coronary heart disease. The present study was designed to test the effects of rosuvastatin on coronary artery atherosclerosis and myocardial fibrosis in SR-B1 (scavenger receptor class B type 1) and apoE (apolipoprotein E) double knockout mice. Three-week-old SR-B1-/-/apoE-/- mice were injected daily with 10 mg/kg of rosuvastatin for 2 weeks. Compared with saline-treated mice, rosuvastatin-treated mice showed increased levels of hepatic PCSK9 (proprotein convertase subtilisin/kexin type-9) and LDLR (low-density lipoprotein receptor) message, increased plasma PCSK9 protein but decreased levels of hepatic LDLR protein and increased plasma total cholesterol associated with apoB (apolipoprotein B) 48-containing lipoproteins. In spite of this, rosuvastatin treatment was associated with decreased atherosclerosis in both the aortic sinus and coronary arteries and reduced platelet accumulation in atherosclerotic coronary arteries. Cardiac fibrosis and cardiomegaly were also attenuated in rosuvastatin-treated SR-B1-/-/apoE-/- mice. Two-week treatment with rosuvastatin resulted in significant decreases in markers of oxidized phospholipids in atherosclerotic plaques. In vitro analysis showed that incubation of bone marrow-derived macrophages with rosuvastatin substantially downregulated cluster of differentiation (CD)36 and inhibited oxidized LDL-induced foam cell formation. Rosuvastatin protected SR-B1-/-/apoE-/- mice against atherosclerosis and platelet accumulation in coronary arteries and attenuated myocardial fibrosis and cardiomegaly, despite increased plasma total cholesterol. The ability of rosuvastatin to reduce oxidized phospholipids in atherosclerotic plaques and inhibit macrophage foam cell formation may have contributed to this protection.

Effect of a novel nutraceutical combination on serum lipoprotein functional profile and circulating PCSK9

BackgroundA beneficial effect on cardiovascular risk may be obtained by improving lipid-related serum lipoprotein functions such as high-density lipoproteins (HDLs) cholesterol efflux capacity (CEC) and serum cholesterol loading capacity (CLC) and by reducing proprotein convertase subtilisin kexin type 9 (PCSK9), independently of lipoprotein concentrations.AimWe aimed to evaluate the effect of an innovative nutraceutical (NUT) combination containing red yeast rice (monacolin K 3.3 mg), berberine 531.25 mg and leaf extract of Morus alba 200 mg (LopiGLIK®), on HDL-CEC, serum CLC and on circulating PCSK9 levels.Materials and methodsTwenty three dyslipidemic subjects were treated for 4 weeks with the above NUT combination. HDL-CEC was measured using specific cell-based radioisotopic assays; serum CLC and PCSK9 concentrations were measured fluorimetrically and by enzyme-linked immunosorbent assay, respectively.ResultsThe NUT combination significantly reduced plasma level of the total cholesterol and low-density lipoprotein cholesterol (−9.8% and −12.6%, respectively). Despite no changes in HDL-cholesterol, the NUT combination improved total HDL-CEC in 83% of the patients, by an average of 16%, as a consequence of the increase mainly of the ATP-binding cassette A1-mediated CEC (+28.5%). The NUT combination significantly reduced serum CLC (−11.4%) while it did not change PCSK9 plasma levels (312.9±69.4 ng/mL vs 334.8±103.5 mg/L, before and after treatment, respectively).ConclusionThe present NUT combination improves the serum lipoprotein functional profile providing complementary beneficial effects, without any detrimental increase of PCSK9 plasma levels.

Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9.

The protein complex proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important target for the prevention and treatment of atherosclerosis and lipid homeostasis. This study investigated the effect of cilostazol on plasma PCSK9 concentrations. We performed a post hoc analysis of two prospective, double-blind, randomized controlled trials including 115 patients of whom 61 received cilostazol 200 mg/day and 54 received placebo for 12 weeks. Linear regression analysis was performed to determine the associations between several parameters and changes in PCSK9 levels. Use of cilostazol, but not placebo, significantly increased plasma PCSK9 concentrations, high-density lipoprotein cholesterol levels, and number of circulating endothelial progenitor cells (EPCs), and decreased triglyceride levels with a trend toward an increase in total cholesterol (TC) levels. A reduction in hemoglobin A1C and an increase in plasma vascular endothelial growth factor and adiponectin levels with cilostazol treatment were also found. Changes in the number of circulating EPCs were positively correlated and the TC concentrations were inversely correlated with changes in the PCSK9 levels. After adjusting for changes in levels of TC and numbers of circulating EPCs and history of metabolic syndrome, use of cilostazol remained independently associated with changes in plasma PCSK9 levels. In conclusion, cilostazol treatment was significantly and independently associated with an increase in plasma PCSK9 levels in patients with peripheral artery disease or at a high risk of cardiovascular disease regardless of background statin use and caused an improvement in some metabolic disorders and levels of vasculo-angiogenic biomarkers.

Evaluation of PCSK9 levels and its genetic polymorphisms in women with polycystic ovary syndrome

Dyslipidemia is one of the common metabolic disorders in Polycystic Ovary Syndrome (PCOS). Proprotein convertase subtilisin kexin type 9 (PCSK9) is a new component of lipid metabolism and correlated to the development of dyslipidemia and atherosclerosis. This protein acts by preventing the recycling of LDL receptors (LDL-r) back to the cell surface and thus generates higher levels of LDLc. The objective of this study was to evaluate the PCSK9 polymorphisms rs505151 (c.2009A>G), rs562556 (c.1420A>G) and rs11206510 (T>C) and plasma PCSK9 levels in PCOS. A group of women with PCOS (n=97), and a group of healthy women (control, n=99) were selected. Biochemical parameters were determined by using Vitros system and polymorphisms were assessed by TaqMan SNP Genotyping Assays. Plasma PCSK9 levels or PCSK9 polymorphisms were not associated with PCOS. The genotype rs11206510TT was associated with higher levels of PCSK9 in both groups. The population investigated (PCOS+control groups) with the rs505151AA genotype presented higher HDLc levels. The GG genotype regarding rs562556 polymorphism was associated with higher HDLc in PCOS group, while the AA genotype carriers had higher plasma testosterone levels when evaluated all women in a same group. The results were the same by comparing recessive and dominant model despite PCOS or both groups altogether. Our results suggest that PCSK9 is not altered specifically in PCOS, but it could be associated with in lipid and androgen metabolism in Brazilian women.

Plasma inducible degrader of the LDLR, soluble low-density lipoprotein receptor, and proprotein convertase subtilisin/kexin type 9 levels as potential biomarkers of familial hypercholesterolemia in children

Familial hypercholesterolemia (FH) in children is under-detected. Plasma biomarkers associated with low-density lipoprotein receptor (LDLR) function could help identifying FH children. We aim to assess the clinical value of inducible degrader of the LDLR (IDOL), soluble LDLR (sLDLR), and proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma concentrations in children with FH compared with control children (CCh). This was a cross-sectional study performed in a Lipid Unit from a University hospital. The participants were 177 children distributed into FH (n=77) and CCh (n=100). Main outcomes were changes in IDOL, sLDLR, and PCSK9 plasma concentrations between children groups; secondary outcomes were the association between IDOL, sLDLR, and PCSK9 and lipid profile determined by 2-dimensional nuclear magnetic resonance. The IDOL levels were higher in FH compared with CCh (P=.007). The PCSK9 levels were elevated in FH (P<.001). The sLDLR levels had no significant differences between groups. IDOL was significantly positively associated to total and LDL cholesterol and ApoB100 but not to LDL particle number. However, a robust correlation with Lp(a) (P=.001) was observed. PCSK9 had the strongest correlation with LDL-associated parameters including particle number. sLDLR was associated with triglyceride levels (P<.001) and triglyceride-rich particles and inversely to LDL size. The IDOL and PCSK9 plasma levels are significantly higher in FH children. Interestingly, sLDLR was associated with atherogenic dyslipidemia components. IDOL concentrations show a robust association with Lp(a) levels. To study the role of plasma biomarkers associated with LDLR expression in FH is warranted.

A Therapeutic Peptide Vaccine Against PCSK9

Vaccination provides a promising approach for treatment of hypercholesterolemia and improvement in compliance. In this study, the appropriate virus-like particle (VLP)-peptide vaccines targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) were screened. The screening criteria of target peptides were as follows: (1) located in catalytic domain of PCSK9, or regulating the binding of PCSK9 and LDL receptors (LDLR); (2) having low/no-similarity when matched with the host proteome; (3) possessing ideal antigenicity and hydrophilicity; (4) including the functional mutation site of PCSK9. It was found that mice vaccinated with VLP -PCSK9 peptide vaccines, especially PCSK9Qβ-003 vaccine, developed high titer IgG antibodies against PCSK9. PCSK9Qβ-003 vaccine obviously decreased plasma total cholesterol in both Balb/c mice and LDLR+/− mice. Also, PCSK9Qβ-003 vaccine decreased plasma PCSK9 level and up-regulated LDLR expression in liver. Additionally, PCSK9Qβ-003 vaccine injection was associated with significant up-regulation of sterol-regulatory element-binding protein-2 (SREBP-2), hepatocyte nuclear factor 1α (HNF-1α), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in LDLR+/− mice. No obvious immune injury was detected in vaccinated animals. The PCSK9Qβ-003 vaccine, therefore, may be an attractive treatment approach for hypercholesterolemia through decreasing cholesterol and regulating lipid homeostasis.

Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation

BackgroundSoluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available. ObjectivesThis study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B2 (11-dh-TxB2), a marker of platelet activation. MethodsWe conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient-years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB2 (n = 852) were measured. The population was divided into tertiles of PCSK9 for the analysis. ResultsThe mean age of patients was 73.5 ± 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB2 were significantly correlated (Spearman's rho: 0.665; p < 0.001). ConclusionsPlasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB2 suggests PCSK9 as a mechanism potentially implicated in platelet activation.

Acute and Chronic Impact of Bariatric Surgery on Plasma LDL Cholesterol and PCSK9 Levels in Patients With Severe Obesity.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol (LDL-C) concentrations. In patients with severe obesity, biliopancreatic diversion with duodenal switch (BPD-DS) surgery induces substantial weight loss and influences lipoprotein metabolism. The effect of BPD-DS on PCSK9 levels is unknown. To determine the acute and chronic impact of BPD-DS on PCSK9 levels and whether the acute impact of BPD-DS could be explained by BPD-DS-associated caloric restriction (CR). PCSK9 levels were measured in 20 men and 49 women (age, 41.5 ± 11.1 years) with severe obesity before, 24 hours, 5 days, and 6 and 12 months after BPD-DS and in a comparable control group (n = 31) at baseline and at 6 and 12 months. PCSK9 levels were also measured during 3-day CR in patients (n = 7) with severe obesity and type 2 diabetes. PCSK9 levels increased 13.4% after 24 hours (248.7 ± 64.8 to 269.7 ± 63.8 ng/mL; P = 0,02) and decreased 9.5% at 12 months compared with baseline (217.6 ± 43.0 ng/mL; P < 0,0001). LDL-C levels decreased 36.2% after 24 hours (2.6 ± 0.7 to 1.7 ± 0.6 mmol/L; P < 0.0001) and 30% at 12 months compared with baseline (1.7 ± 0.5 mmol/L; P < 0.0001). Compared with baseline levels, PCSK9 levels were lower at day 2 but not at day 1 or 3 after CR. BPD-DS is associated with acute increases in PCSK9 levels that do not appear to be explained by CR but may be due to an acute response following surgery. BPD-DS induces chronic reductions in both PCSK9 and LDL-C levels.

Plasma PCSK9 levels are unrelated to arterial stiffness in a community-based, 4.8-year prospective study.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important circulating serine protease in low-density lipoprotein cholesterol (LDL-C) metabolism. Increased plasma PCSK9 levels lead to increased plasma levels of LDL-C and an increased risk of cardiovascular disease (CVD). LDL-C is positively correlated with arterial stiffness, a surrogate endpoint of CVD. However, whether plasma levels of PCSK9 could influence arterial stiffness is still unclear. Our study examined the relationship between plasma levels of PCSK9 and arterial stiffness (carotid-femoral pulse wave velocity (cf-PWV)) in a community-based population. We analysed the measurements of baseline plasma PCSK9 levels and both baseline and follow-up cf-PWV in 1447 subjects in a 4.8-year longitudinal study. Pearson's correlation analyses revealed that plasma levels of PCSK9 were not correlated with cf-PWV. Additionally, multiple linear regression analyses using cf-PWV as the dependent variable and adjusting for several potential confounders showed that plasma PCSK9 levels were not significantly correlated with cf-PWV. Thus, our study could not prove an independent relationship between plasma levels of PCSK9 and arterial stiffness.