Variations of the proprotein convertase subtilisin/kexin type 9 gene in coronary artery disease.
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ABSTRACT:
SUBMITTER: Chiang SM
PROVIDER: S-EPMC7140201 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Variations of the proprotein convertase subtilisin/kexin type 9 gene in coronary artery disease.
Chiang Shih-Min SM Yang Yi-Sun YS Yang Shun-Fa SF Tsai Chin-Feng CF Ueng Kwo-Chnag KC
The Journal of international medical research 20190405 1
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Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) is suggested as a novel factor associated with coronary artery disease (CAD). However, few studies have comprehensively evaluated plasma PCSK9 with cardiovascular risk till now. Hence, we aimed to prospectively investigate the association between baseline PCSK9 and cardiovascular risk graded with number of risk factors (RFs), coronary severity, and outcomes in patients with stable CAD.Baseline characteristics and biomarkers were measured in 616 consecutive, nontreated patients with stable CAD. Coronary severity was measured using SYNTAX, Gensini, and Jeopardy scoring systems. Patients were then received treatment and followed for a median of 17 months. The primary endpoints were cardiac death, stroke, myocardial infarction (MI), post-discharge revascularization, or unstable angina (UA).Overall, follow-up data were obtained from 603 patients. A total of 72 (11.9%) patients presented with at least 1 major adverse cardiovascular event (MACE) (4 cardiac deaths, 4 strokes, 6 MIs, 28 revascularizations, and 30 UAs). At baseline, PCSK9 was increased with an increasing number of RFs and positively associated with coronary severity scores (P < 0.05, all). After follow-up, those with MACE had a higher baseline PCSK9, hs-CRP, and coronary scores than those without (P < 0.05, all). Multivariate analysis showed that PCSK9, hs-CRP, and coronary scores were independently predictive for MACEs (P < 0.05, all). Interestingly, more significant predictive values of PCSK9 in medical-alone-treated population but no such associations in revascularization-treated patients were found.Together, plasma PCSK9, as well as hs-CRP and coronary scores, could independently predict MACEs in patients with stable CAD.
| S-EPMC5291644 | biostudies-literature
Project description:ObjectiveThe study aims to explore the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) level and saphenous vein grafts disease (SVGD) after coronary artery bypass grafting (CABG).DesignA cross-sectional study.SettingA secondary hospital in Tianjin City, China.ParticipantsA total of 231 participants were included in the study. Inclusion criteria were as follows: age ≥18 years, previous CABG surgery at least 12 months ago, at least one SVG for bypass during CABG, abnormal non-invasive test results or recurrent stable angina pectoris by coronary angiography indications, and willing to participate and sign informed consent. Participants with any of the following were excluded from the study: congenital valvular disease, decompensated heart failure, anaemia defined as a haemoglobin level of <12 g/dL in women or <13 g/dL in men, malignant neoplasms, renal failure, severe hepatic disease, thyroid disease, acute or chronic inflammatory disease and chronic obstructive lung disease.Primary outcome measureSVGD was defined as at least one SVG with significant stenosis (≥50%). Circulating PCSK9 levels were measured using commercial ELISA kits according to the manufacturer's instructions.ResultsThe mean PCSK9 level in the SVGD group was significantly higher than that in the patent group (275.2±38.6 vs 249.3±37.7, p<0.01). The multivariate logistic regression model revealed a significant association between serum PCSK9 and SVGD (OR 2.08, 95% CI 1.46-2.95) per 1 SD increase in serum PCSK9.ConclusionsThe present study is the first to identify an independent association between PCSK9 and late SVGD after adjustment for established cardiovascular risk factors. A multicentre prospective cohort study with large sample size should be conducted in the future to further research this relationship.
| S-EPMC6089317 | biostudies-literature
Project description:AimsProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably alter the lipid profile. We sought to examine the rates of ischaemic stroke and neurocognitive deficits in patients treated with and without PCSK9 inhibitors.Methods and resultsRandomized controlled trials (RCTs) reporting rates of ischaemic stroke and neurocognitive deficits in patients using PCSK9 inhibitors were identified. Standard meta-analysis techniques were used to compare these outcomes among patients treated with and without PCSK9 inhibitors and the two US Food and Drug Administration-approved PCSK9 inhibitors, evolocumab and alirocumab. The results were presented in terms of risk ratio (RR) with 95% confidence intervals (CIs). Sixteen RCTs with 39 104 patients were included. Evolocumab was used in six RCTs with 33 450 patients, whereas alirocumab was used in 10 RCTs with 5654 patients. We observed a significantly lower risk of ischaemic stroke among those treated with PCSK9 inhibitors (RR 0.77, 95% CI 0.64-0.93) when compared with those without. We did not observe any difference in the risk of neurocognitive deficits between the aforementioned groups (RR 1.11, 95% CI 0.93-1.32). The lower stroke risk in the PCSK9 inhibitors group was driven by evolocumab studies. We observed no difference in the risk of neurocognitive deficits among evolocumab and alirocumab when compared with no PCSK9 inhibitors group.ConclusionTreatment with PCSK9 inhibitors significantly lowers the risk of ischaemic stroke, without any increased risk of neurocognitive deficits. PCSK9 inhibitors are neuroprotective due to the decrease in ischaemic-mediated neurovascular events and should be considered cognitively innocuous medications.
| S-EPMC5884103 | biostudies-literature
Project description:High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeostasis by targeting the low-density lipoprotein receptor (LDLR) for degradation. PCSK9 is mostly expressed in liver, which is one of the most common sites for metastatic disease. To reveal the function of PCSK9 and also evaluate the impact of cholesterol in liver metastasis development, B16F1 melanoma cells were injected into wild-type (WT) and Pcsk9(-/-) mice to induce liver metastasis. On chow diet, Pcsk9(-/-) mice harbored two-fold less liver metastases than WT mice. This decrease is related to low cholesterol levels in Pcsk9(-/-) mice, as the protection was lost after normalizing Pcsk9(-/-) cholesterol levels by a 2-week high cholesterol diet. Furthermore, a prolongation of this diet strongly increased metastasis in both genotypes, suggesting that high cholesterol levels promote metastatic progression. The protective effect of the PCSK9 deficiency is also associated with increased apoptosis in liver stroma and metastases. Tumor necrosis factor.α (TNFα) mRNA and protein were, respectively, higher in liver stroma and plasma of injected mice, likely increasing the apoptotic TNFα signaling. Furthermore, the anti-apoptotic factor B-cell lymphoma 2 was downregulated. TNFα regulation is LDLR-independent, as its mRNA level was similarly upregulated in mice lacking both PCSK9 and LDLR. Our findings show that PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol levels and by possibly enhancing TNFα-mediated apoptosis.
| S-EPMC3540939 | biostudies-literature
Project description:Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.
| S-EPMC6538876 | biostudies-literature
Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the degradation of low-density lipoprotein (LDL) receptors; it has been proved that its inhibition improves cardiovascular outcomes in patients with established atherosclerotic cardiovascular disease (ASCVD). Herein, we review the current status of PCSK9 inhibitors in clinical practice and the future scope of PCSK9 inhibition. The results of two recent large clinical trials reveal that two PCSK9 monoclonal antibodies evolocumab and alirocumab reduce the risk of a cardiovascular event on top of background statin therapy in patients with stable ASCVD and those with recent acute coronary syndrome, respectively. However, there are several ongoing concerns regarding the efficacy in reducing mortality, cost-effectiveness, and long-term safety of extremely low LDL cholesterol levels with PCSK9 inhibition. The results of ongoing cardiovascular outcomes trials with PCSK9 monoclonal antibodies for primary prevention and with small interfering RNA to PCSK9 for secondary prevention may help to shape the use of this new therapeutic class.
| S-EPMC7487297 | biostudies-literature
Project description:BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors.ObjectivesIn this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events.MethodsWe investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile.ResultsTotal, mature, and furin-cleaved PCSK9 levels were associated with non-high-density lipoprotein cholesterol (all P < 0.001) and systolic blood pressure (P = 0.001, P = 0.004, and P < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) (P < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; P = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; P = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; P = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; P = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; P = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; P = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; P = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; P = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; P = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; P = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; P = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; P = 0.72]), respectively.ConclusionsFurin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events.
| S-EPMC9627806 | biostudies-literature
Project description:Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, combining genetic, transcriptomic and proteomic data from three vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms, with patient clinical parameters and immunohistochemistry of vascular biopsies. Apart from PCSK4, all PCSK family members lie in genetic regions containing variants associated with human cardiovascular traits. Transcriptomic analyses revealed that FURIN, PCSK5, MBTPS1 were downregulated, while PCSK6/7 were upregulated in plaques vs. control arteries. In abdominal aneurysms, FURIN, PCSK5, PCSK7, MBTPS1 were downregulated, while PCSK6 was enriched in diseased media. In thoracic aneurysms, only FURIN was significantly upregulated. Network analyses of the upstream and downstream pathways related to PCSKs were performed on the omics data from vascular biopsies, revealing mechanistic relationships between this protein family and disease. Cell type correlation analyses and immunohistochemistry showed that PCSK transcripts and protein levels parallel each other, except for PCSK9 where transcript was not detected, while protein was abundant in vascular biopsies. Correlations to clinical parameters revealed a positive association between FURIN plaque levels and serum LDL, while PCSK6 was negatively associated with Hb. PCSK5/6/7 were all positively associated with adverse cardiovascular events. Our results show that PCSK6 is abundant in plaques and abdominal aneurysms, while FURIN upregulation is characteristic for thoracic aneurysms. PCSK9 protein, but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Integrating our results lead to the development of a novel 'molecular' 5D framework. Here, we conducted the first integrative study of the proprotein convertase family in this context. Our results using this translational pipeline, revealed primarily PCSK6, followed by PCSK5, PCSK7 and FURIN, as proprotein convertases with the highest novel therapeutic potential.
| S-EPMC9520287 | biostudies-literature
Project description:BackgroundStudies had investigated the associations between proprotein convertase subtilisin/kexin type 9 (PCSK9) E670G polymorphism and coronary artery disease (CAD) and lipid levels, but the results were controversial. Thus, we performed this meta-analysis to investigate the association between PCSK9 E670G polymorphism and lipid levels and the susceptibility to CAD.MethodsAll relevant articles according to the inclusion criteria were retrieved and included in the present meta-analysis. Odds ratios (ORs) with 95 % confidence interval (CI) were used to analyze the strength of the association between PCSK9 E670G polymorphism and the susceptibility to CAD. At the same time, the pooled standardized mean difference (SMD) with 95 % CI was used for the meta-analysis of PCSK9 E670G polymorphism and lipid levels. The publication bias was examined by using Begg's funnel plots and Egger's test.ResultsA total of seventeen studies met the inclusion criteria. For CAD association, the pooled effects indicated that the G allele carriers had higher risk of CAD than non-carriers in dominant genetic model (OR:1.601, 95 % CI: 1.314-1.951, P < 0.001), as well as in allelic genetic model (OR: 1.546, 95 % CI: 1.301-1.838, P < 0.001). When the subgroup analysis stratified by ethnicity and HWE was performed, the positive result existed in most of the subgroups. For lipid levels association, the pooled effects indicated that the G allele carriers had higher TC and LDL-C levels than the non-carriers (for TC, SMD: 0.126, 95 % CI: 0.023-0.229, P = 0.016; for LDL-C, SMD: 0.170, 95 % CI: 0.053-0.287, P = 0.004, respectively). There was no difference in the levels of TG and HDL-C between the G carriers and the non-carriers in the whole population (SMD: 0.031, 95 % CI: -0.048-0.110, P = 0.440; SMD: -0.123, 95 % CI: -0.251-0.006, P = 0.061, respectively). When the studies were stratified by ethnicity and type of study, the G carriers had higher TC levels than the non-carriers (SMD: 0.126, 95 % CI: 0.014-0.238, P = 0.027) in the non-Asian subgroup. The similar results existed in cohort subgroup. The association between PCSK9 E670G polymorphism and LDL-C levels was significant in all subgroups. Meanwhile, the G carriers had higher TG levels than the non-carriers (SMD: 0.113, 95 % CI: 0.012-0.214, P = 0.028) in the case-control subgroup. AG + GG genotypes had lower HDL-C levels than AA genotype in Asian subgroup (SMD: -0.224, 95 % CI: -0.423- -0.025, P = 0.027) and in case-control subgroup (SMD: -0.257, 95 % CI: -0.467--0.048, P = 0.016).ConclusionsThe present meta-analysis concluded that PCSK9 E670G polymorphism was associated with CAD risk and lipid levels.
| S-EPMC4650262 | biostudies-literature
Project description: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.
| S-EPMC5746124 | biostudies-literature