Journal articles: 'PCSK7'

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Parvaz, Najmeh, and Zahra Jalali. "Molecular evolution of PCSK family: Analysis of natural selection rate and gene loss." PLOS ONE 16, no. 10 (October 28, 2021): e0259085. http://dx.doi.org/10.1371/journal.pone.0259085.

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Proprotein convertases subtilisin kexins are serine endoproteases, playing critical roles in the biological functions, including lipid, glucose, and bile acid metabolism, as well as cell proliferation, migration, and metastasis. Experimental studies have demonstrated the physiological functions of PCSKs and their association with diseases; however, studies on the evolutionary history and diversification of these proteins are missing. In the present research, a bioinformatics study was conducted on the molecular evolution of several PCSKs family members and gene loss events across placental mammalian. In order to detect evolutionary constraints and positive selection, the CodeML program of the PAML package was used. The results showed the positive selection to occur in PCSK1, PCSK3, PCSK5, and PCSK7. A decelerated rate of evolution was observed in PCSK7, PCSK3, and MBTPS1 in Carnivores compared to the rest of phylogeny, and an accelerated evolution of PCSK1, PCSK7, and MBTPS1 in Muridae family of rodents was found. Additionally, our results indicated pcsk9 gene loss in 12 species comprising Carnivores and bats (Chiroptera). Future studies are required to evaluate the functional relevance and selective evolutionary advantages associated with these modifications in PCSK proteins during evolution.

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Dongiovanni, Paola, Marica Meroni, Guido Baselli, Rosellina M. Mancina, Massimiliano Ruscica, Miriam Longo, Raffaela Rametta, et al. "PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients." Journal of Lipid Research 60, no. 6 (March 27, 2019): 1144–53. http://dx.doi.org/10.1194/jlr.p090449.

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Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P < 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (P < 0.05). The rs236918 C allele was associated with upregulation of a new “intra-PCSK7” long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P < 0.01), which correlated with triglycerides (P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β pathway activation, and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.

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Malakootian, Mahshid, Parisa Naeli, Seyed Javad Mowla, and Nabil G. Seidah. "Post-Transcriptional Effects of miRNAs on PCSK7 Expression and Function: miR-125a-5p, miR-143-3p, and miR-409-3p as Negative Regulators." Metabolites 12, no. 7 (June 23, 2022): 588. http://dx.doi.org/10.3390/metabo12070588.

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The regulatory mechanism of PCSK7 gene is still unknown, although its encoded protein PC7 is the most ancient and highly conserved of all proprotein convertases and exhibits enzymatic and non-enzymatic functions in liver triglyceride regulation. Bioinformatics algorithms were used to predict regulatory microRNAs (miRNAs) of PCSK7 expression. This led to the identification of four miRNAs, namely miR-125a-5p, miR-143-3p, miR-409-3p, and miR-320a-3p, with potential binding sites on the 3′-untranslated region (3′-UTR) of human PCSK7 mRNA. The expression patterns of these miRNAs and PCSK7 mRNA were assessed in three different cell lines with quantitative polymerase chain reaction (qPCR), which revealed reciprocal expression patterns between the expression levels of the four selected miRNAs and PCSK7. Next, the interactions and effects of these miRNAs on PCSK7 expression levels were investigated via cell-based expression analysis, dual-luciferase assay, and Western blot analysis. The data revealed that PCSK7 mRNA levels decreased in cells transfected with vectors overexpressing miR-125a-5p, miR-143-3p, and miR-409-3p, but not miR-320a-3p. The dual-luciferase assay demonstrated that the above three miRNAs could directly interact with putative target sites in PCSK7 3′-UTR and regulate its expression, whereas miR-320-3p exhibited no interaction. Western blot analysis further revealed that the overexpression of miR-125a-5p in Huh7 cells inhibits the expression and ability of PC7 to cleave human transferrin receptor 1. Our results support a regulatory role of these miRNAs on PCSK7 expression and function and open the way to assess their roles in the regulation of PC7 activity in vivo in the development of hepatic steatosis.

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Kupcinskas, Juozas, Irena Valantiene, Greta Varkalaitė, Ruta Steponaitiene, Jurgita Skieceviciene, Jolanta Sumskiene, Vitalija Petrenkiene, et al. "PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population." Journal of Gastrointestinal and Liver Diseases 26, no. 1 (March 1, 2017): 37–43. http://dx.doi.org/10.15403/jgld.2014.1121.261.pnp.

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Background & Aims: Genome-wide association studies have revealed an association between the risk of developing liver fibrosis or cirrhosis and the single nucleotide polymorphisms (SNPs) of the PNPLA3, RNF7, MERTK and PCSK7 genes. We aimed to validate these results in an Eastern European population.Methods: We evaluated the associations between the PNPLA3 (rs738409), RNF7 (rs16851720), MERTK (rs4374383) and PCSK7 (rs236918) variants and liver fibrosis and cirrhosis in a series of consecutive patients recruited at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, during the period 2012-2015. The study included 317 individuals with liver cirrhosis, 154 individuals with liver fibrosis, and 498 controls. The studied SNPs were determined using RT-PCR TaqMan assays.Results: MERTK and PCSK7 SNPs were not associated with liver fibrosis or cirrhosis. The PNPLA3 SNP rs738409 was associated with a higher risk of developing liver fibrosis (aOR: 1.65, P=0.001) and cirrhosis (aOR: 1.92, P=5.57*10-7). PNPLA3 genotypes were also associated with higher risk of developing liver fibrosis and cirrhosis in dominant (aOR: 1.98, P=2.20*10-5; aOR: 1.67, P=0.008, respectively) and recessive (aOR: 3.94, P=5.16*10-5; aOR: 3.02, P=0.003, respectively) models. RNF7 rs16851720 was associated with liver cirrhosis comparing CC vs. AA + CA genotypes (aOR: 0.26, P=0.020).Conclusion: Our study showed that PNPLA3 rs738409 and RNF7 rs16851720 confer an increased risk of developing liver fibrosis and cirrhosis in this Eastern European population, while the MERTK and PCSK7 SNPs are not associated with these conditions.Abbreviations: GWAS: Genome-wide association studies; HBV: hepatitis B virus; HCV: hepatitis C virus; HH: hereditary hemochromatosis; MERTK: proto-oncogene tyrosine-protein kinase MER; NAFLD: non-alcoholic fatty liver disease; PCSK7: proprotein convertase 7; PNPLA3: patatin-like phospholipase domain containing 3; RNF7: SAG sensitive to apoptosis gene; SNP: single nucleotide polymorphism.

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Vargas-Alarcón, Gilberto, Oscar Pérez-Méndez, Héctor González-Pacheco, Julián Ramírez-Bello, Rosalinda Posadas-Sánchez, Galileo Escobedo, and José Manuel Fragoso. "The rs508487, rs236911, and rs236918 Genetic Variants of the Proprotein Convertase Subtilisin–Kexin Type 7 (PCSK7) Gene Are Associated with Acute Coronary Syndrome and with Plasma Concentrations of HDL-Cholesterol and Triglycerides." Cells 10, no. 6 (June 9, 2021): 1444. http://dx.doi.org/10.3390/cells10061444.

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Dyslipidemia has a substantial role in the development of acute coronary syndrome (ACS). Previous reports, including genome-wide associations studies (GWAS), have shown that some genetic variants of the proprotein convertase subtilisin–kexin type 7 (PCSK7) gene are associated with plasma lipid levels. In the present study, we evaluated whether PCSK7 gene polymorphisms are significantly associated with the plasma lipid profile and ACS. Three PCSK7 gene polymorphisms (rs508487 T/C, rs236911 C/A, and rs236918 C/G) were determined using TaqMan genotyping assays in a group of 603 ACS patients and 622 healthy controls. The plasma lipid profile was determined in the study groups by enzymatic/colorimetric assays. Under the recessive model, the rs236918 C allele was associated with a high risk of ACS (OR = 2.11, pC = 0.039). In the same way, under the recessive and additive models, the rs236911 C allele was associated with a high risk of ACS (OR = 1.95, pC = 0.037, and OR = 1.28, pC = 0.037, respectively). In addition, under the co-dominant model, the rs508487 T allele was associated with a higher risk of ACS (OR = 1.78, pC = 0.010). The CCC and TCC haplotypes were associated with a high risk of ACS (OR = 1.21, pC = 0.047, and OR = 1.80, pC = 0.001, respectively). The rs236911 CC and rs236918 CC genotypes were associated with lower high-density lipoproteins-cholesterol (HDL-C) plasma concentrations, whereas the rs236911 CC genotype was associated with a higher concentration of triglycerides, as demonstrated in the control individuals who were not receiving antidyslipidemic drugs. Our data suggest that the PCSK7 rs508487 T/C, rs236911 C/A, and rs236918 C/G polymorphisms are associated with the risk of developing ACS, and with plasma concentrations of HDL-C and triglycerides.

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Ashraf, Yahya, Stéphanie Duval, Vatsal Sachan, Rachid Essalmani, Delia Susan‐Resiga, Anna Roubtsova, Josée Hamelin, et al. "Proprotein convertase 7 (PCSK7) reduces apoA‐V levels." FEBS Journal 287, no. 16 (January 29, 2020): 3565–78. http://dx.doi.org/10.1111/febs.15212.

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Tobiasch, Moritz, Benedikt Schaefer, André Viveiros, Herbert Tilg, Ivo Graziadei, and Heinz Zoller. "Survival in HFE hemochromatosis: influence of polymorphisms in HSD17B13, GNPAT, and PCSK7." Journal of Hepatology 73 (August 2020): S551—S552. http://dx.doi.org/10.1016/s0168-8278(20)31575-0.

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Schwienbacher, Christine, Alice Serafin, Alessandra Zanon, Peter P. Pramstaller, Irene Pichler, and Andrew A. Hicks. "Involvement of proprotein convertase PCSK7 in the regulation of systemic iron homeostasis." Hepatology 58, no. 5 (October 1, 2013): 1860–61. http://dx.doi.org/10.1002/hep.26392.

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Carr, Rotonya M., and Nicholas O. Davidson. "Building bridges: PCSK7 as a NAFLD candidate gene connecting hepatic inflammation with hypertriglyceridemia." Journal of Lipid Research 60, no. 6 (April 25, 2019): 1067–68. http://dx.doi.org/10.1194/jlr.c094888.

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Gagnon, Jeffrey, Janice Mayne, Majambu Mbikay, John Woulfe, and Michel Chrétien. "Expression of PCSK1 (PC1/3), PCSK2 (PC2) and PCSK3 (furin) in mouse small intestine." Regulatory Peptides 152, no. 1-3 (January 2009): 54–60. http://dx.doi.org/10.1016/j.regpep.2008.07.006.

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Seidah, Nabil G., Antonella Pasquato, and Ursula Andréo. "How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?" Viruses 13, no. 7 (June 25, 2021): 1229. http://dx.doi.org/10.3390/v13071229.

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Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.

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Oexle, Konrad, Janina S. Ried, Andrew A. Hicks, Toshiko Tanaka, Caroline Hayward, Mathias Bruegel, Martin Gögele, et al. "Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels." Human Molecular Genetics 20, no. 5 (December 10, 2010): 1042–47. http://dx.doi.org/10.1093/hmg/ddq538.

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Buch, S., M. J. Way, F. Stickel, E. Ryan, H. Zoller, W. J. H. Griffiths, A. McQuillin, et al. "Variants in TM6SF2 and PCSK7 are risk factors for the development of cirrhosis in people with genetic haemochromatosis." Journal of Hepatology 66, no. 1 (2017): S179—S180. http://dx.doi.org/10.1016/s0168-8278(17)30644-x.

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Buch, Stephan, Aneesh Sharma, Eleanor Ryan, Christian Datz, William Griffiths, Michael Way, Thomas Buckley, et al. "Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in people with hereditary haemochromatosis." Journal of Hepatology 73 (August 2020): S63—S64. http://dx.doi.org/10.1016/s0168-8278(20)30666-8.

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Alieva, R. B., S. U. Hoshimov, Sh S. Ahmedova, F. M. Bekmetova, A. B. Shek, and R. D. Kurbanov. "ASSOTIATION OF THE GENETIC POLYMORPHISM E670G OF THE PCSK-9 AND THE SEVERITY OF THE CAROTID ATHEROSCLEROSIS IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA IN UZBEK POPULATION." Eurasian heart journal, no. 3 (September 30, 2019): 34–41. http://dx.doi.org/10.38109/2225-1685-2019-3-34-41.

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Objective: to study the severity of carotid artery atherosclerosis in patients with heterozygous familial hypercholesterolemia in the Uzbek population, depending on the level of PCSK-9 and the genetic polymorphism E670G of the PCSK-9 gene.Material and methods. The study included 57 patients with chronic stable coronary artery disease (SCAD) and familial heterozygous hypercholesterolemia (HeFH, group I). The comparison group consisted of 144 patients with SCAD without HeFH divided into two subgroups: A - statin free before the research (n=63) and B (n=81) who took it as outpatients; control group consisted of 17 healthy people. The level of proprotein convertase subtilisin-kexin type 9 (PCSK-9) was measured with Human Proprotein Convertase 9/PCSK9 ELISA Kit (MULTI SCIENCE, China). The genetic typing of PCSK9 E670G (rs505151) polymorphism was performed by means of the PCR-RFLP method.Results. A comparison of the results of duplex scanning of carotid arteries in patients with HeFH showed that the carotid intima-media thickness (CIMT) on the left (1.14±0.18 mm, P<0.01) and on the right (1.15±0.16 mm, P<0.01) was higher, than in the comparison group: 1.05±0.17 mm and 1.04±0.18 mm, respectively. The studies revealed a positive correlation between the incidence of Myocardial infarction (MI) in the history in patients with HeFH and the (r=0.38, P<0.05). The CIMT also correlated with an increase in the concentration of PCSK9 (r = 0.31, P <0.05) in the blood and the carriage of the G allele of polymorphism E670G (r = 0.39, P <0.05) of the PCSK9 gene.Conclusion. Inpatientswithheterozygousfamilialhypercholesterolemia in the Uzbek population a direct correlation was established between Myocardial infarction in the history, the carotid intima-media thickness, an increase in the concentration of PCSK-9 in the blood and the carriage of the G allele of E670G polymorphism of the PCSK9 gene, that allows them to be used as prognostic markers for the risk of development of cardiovascular complications.

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Buch, Stephan, Felix Stickel, Heinz M. Zoller, Sabina Gallati, Christoph Österreicher, Elmar Aigner, Christoph Sarrazin, et al. "592 Evaluation of Genome-Wide Loci of Iron Metabolism in Hereditary Hemochromatosis Identifies Pcsk7 as a Predictor of Liver Cirrhosis." Gastroenterology 142, no. 5 (May 2012): S—919. http://dx.doi.org/10.1016/s0016-5085(12)63567-7.

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Stickel, F., S. Buch, H. Zoller, S. Gallati, C. (Österreicher, A. Finkenstedt, A. Stadlmayr, et al. "134 EVALUATION OF GENOME-WIDE LOCI OF IRON METABOLISM IN HEREDITARY HEMOCHROMATOSIS IDENTIFIES PCSK7 AS A PREDICTOR OF LIVER CIRRHOSIS." Journal of Hepatology 56 (April 2012): S58. http://dx.doi.org/10.1016/s0168-8278(12)60148-2.

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Jin, Jaeho, Wooyeon Jo, Ji Heon Noh, and Sang Ki Lee. "PCSK9 and LDL-C: The Role of Exercise." Exercise Science 29, no. 4 (November 30, 2020): 347–51. http://dx.doi.org/10.15857/ksep.2020.29.4.347.

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PURPOSE: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a pivotal regulator of low lipoprotein-cholesterol (LDL-C) and LDL receptor (LDLR) metabolism, and the interest in PCSK9 has increased in cardiovascular diseases. Exercise reduces blood LDL-C via PCSK9-LDLR pathway in the liver and the vasculature. However, the mechanism of exercise-induced inhibition of PCSK is unclear. The aim of this review is to describe the role of exercise on PCSK9-LDLR axis in cardiovascular diseases.METHODS:This study review 34 previous studies focusing on the effect of exercise on PCSK9 in the human and animal.RESULTS:The effects of exercise and lifestyle intervention on hepatic and circulating PCSK9 are controversial. However, exercise consistently increases hepatic LDLR, and inhibits atherosclerosis via suppression of PCSK9 and LOX-1 in atherosclerotic region.CONCLUSIONS: Even though experimental data are still very limited, exercise training can improves blood LDL-C via inhibition of PCSK9 and enhancement of LDLR in liver and vasculature. The study of exercise on PCSK9 are urgently needed.

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Stickel, F., S. Buch, H. Zoller, R. Hultcrantz, S. Gallati, C. Osterreicher, A. Finkenstedt, et al. "Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis." Human Molecular Genetics 23, no. 14 (February 20, 2014): 3883–90. http://dx.doi.org/10.1093/hmg/ddu076.

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Turpeinen, Hannu, Anna Oksanen, Virpi Kivinen, Sampo Kukkurainen, Annemari Uusimäki, Mika Rämet, Mataleena Parikka, Vesa P. Hytönen, Matti Nykter, and Marko Pesu. "Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)." Journal of Biological Chemistry 288, no. 51 (October 31, 2013): 36610–23. http://dx.doi.org/10.1074/jbc.m113.453183.

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Röhl, Samuel, Bianca E. Suur, Mariette Lengquist, Till Seime, Kenneth Caidahl, Ulf Hedin, Anders Arner, Ljubica Matic, and Anton Razuvaev. "Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice." Cells 9, no. 4 (April 18, 2020): 1009. http://dx.doi.org/10.3390/cells9041009.

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Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with inflammation, extracellular matrix remodeling and cytokines. Here, we hypothesize that PCSK6 could be involved in flow-mediated vascular remodeling and aim to evaluate its role in the physiology of this process using knockout mice. Pcsk6−/− and wild type mice were randomized into control and increased blood flow groups and induced in the right common carotid artery (CCA) by ligation of the left CCA. The animals underwent repeated ultrasound biomicroscopy (UBM) examinations followed by euthanization with subsequent evaluation using wire myography, transmission electron microscopy or histology. The Pcsk6−/− mice displayed a flow-mediated increase in lumen circumference over time, assessed with UBM. Wire myography revealed differences in the flow-mediated remodeling response detected as an increase in lumen circumference at optimal stretch with concomitant reduction in active tension. Furthermore, a flow-mediated reduction in expression of SMC contractile markers SMA, MYH11 and LMOD1 was seen in the Pcsk6−/− media. Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow.

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Shu, Xin, Jiaqi Wu, Tao Zhang, Xiaoyu Ma, Zuoqin Du, Jin Xu, Jingcan You, et al. "Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes PCSK9–Dependent Adipose Insulin Resistance." Nutrients 14, no. 24 (December 14, 2022): 5314. http://dx.doi.org/10.3390/nu14245314.

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Statin treatment is accepted to prevent adverse cardiovascular events. However, statin therapy has been reported to be dose-dependently associated with increased risk for new-onset type 2 diabetes mellitus (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in adipose tissue and is positively correlated with lipid metabolism. It is, however, unknown if PCSK9 participates in adipocyte insulin resistance occurring as a result of statin use. Our goal was to use an in vitro adipose tissue explant approach to support the hypothesis that PCSK9 regulates statin-induced new-onset T2DM. Studies were performed using Pcsk−/− and C57Bl/6J control mice. Pcsk9−/− and control mice were fed a high-fat diet to affect a state of chronically altered lipid metabolism and increased PCSK9. Epididymal fat was excised and incubated with atorvastatin (1 µmol/L) in the absence and presence of insulin or geranylgeranyl pyrophosphate (GGPP). PCSK9 mRNA was evaluated using quantitative rtPCR. We further examined the effects of atorvastatin on insulin-mediated AKT signaling in adipose tissue explants by immunoblotting. Atorvastatin was found to upregulate PCSK9 gene expression in adipose tissue. The metabolic intermediate GGPP is required to downregulate PCSK9 expression. PCSK9 deficiency protects against statin-induced impairments in insulin signaling. Moreover, supplementation with GGPP reversed atorvastatin-induced suppression of insulin signaling. Furthermore, the basal and atorvastatin-stimulated release of free fatty acids was observed in adipose tissue from wild-type mice but not PCSK9 deficient mice. Collectively, we describe a novel mechanism for PCSK9 expression in adipose tissue that could mediate statin-impaired adipose insulin resistance.

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Kurano, Makoto, Kazuhisa Tsukamoto, Shigeo Kamitsuji, Naoyuki Kamatani, Masumi Hara, Toshio Ishikawa, Bong-Jo Kim, Sanghoon Moon, Young Jin Kim, and Tamio Teramoto. "Genome-wide association study of serum lipids confirms previously reported associations as well as new associations of common SNPs within PCSK7 gene with triglyceride." Journal of Human Genetics 61, no. 5 (January 14, 2016): 427–33. http://dx.doi.org/10.1038/jhg.2015.170.

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Kajingulu, François-Pantaléon Musungayi, Aliocha Natuhoyila Nkodila, Jean-Robert Rissassy Makulo, Vieux Momeme Mokoli, Yannick Mopango Engole, Pepe Mfutu Ekulu, Justine Busanga Bukabau, et al. "Proprotein Convertase Subtilisin/Kexin 9 level is independently associated with 10-year cardiovascular risk in blood donors in Kinshasa: A cross-sectional study based on Framingham predictive equation." Annales Africaines de Medecine 15, no. 3 (July 1, 2022): e4643-e4654. http://dx.doi.org/10.4314/aamed.v15i3.2.

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Context and objective: Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) plays an important role in lipid homeostasis. The present study aimed to determine whether PCSK9 is a potential cardiovascular risk (CVR) factor among apparently healthy people. Methods: A cross-sectional study was conducted between August 2016 and July 2020 in the City of Kinshasa, Democratic Republic of the Congo. Volunteer and regular blood donors from the Catholic medical network (Bureau Diocésain des OEuvres Médicales [BDOM]/Kinshasa) were enrolled in this study. Serum PCSK9 and lipid levels were measured by ELISA and enzymatic colorimetric method, respectively. Framingham’s predictive equation was used for predicting cardiac events. Pearson's correlation coefficients (r) were calculated to assess the association between the different lipid fractions and PCSK-9. The search for the determinants of 10 year-risk of a high cardiovascular event was carried out using the cultivariate binary logistic regression model. Results: Of 296 subjects included in the present study, 264 (89.1 %) had low and 32 (10.8 %) high CVR. Age ≥ 50 years (aOR 5), low HDL-c (aOR 5), high LDL-c (aOR 6), hypertriglyceridemia (aOR 4), and belonging to the 3rd tertile of PCSK9 ((aOR 4.4) emerged as independent determinants of high CVR. Conclusion: High plasma levels of PCSK9 are associated with high CVR in apparently healthy people. Prospective studies in the general population to confirm this Framingham cardiovascular prediction are needed. French title: Le taux de Proprotein Convertase Subtilisin/Kexin 9 est indépendamment associé au risque cardiovasculaire à 10 ans chez les donneurs de sang à Kinshasa : Etude transversale basée sur Contexte et objectif: La Proprotéine Convertase Subtilisine Kexin type 9 (PCSK9) est importante dans l'homéostasie des lipides. Cette étude visait à établir le rôle potentiel de PCSK9 comme facteur de risque cardiovasculaire (RCV). Méthodes. L’enquête transversale couvrant la période d’août 2016 à juillet 2020 a été conduite dans la ville de Kinshasa (RD Congo), sur des donneurs de sang volontaires et réguliers au sein du réseau médical catholique (BDOM). La technique Elisa a permis l’analyse de PCSK9 sérique et le taux des lipides était dosé par la méthode enzymatique colorimétrique. L'équation de prédiction des événements CV a recourru à la méthode Framingham. La corrélation entre le taux des lipides sériques et le PCSK-9 a été faite à l’aide de corrélation linéraire de Pearson. La régression logistique binaire multivariée a déterminé le niveau du risque futur des événements CV. Résultats: 264/296 sujets (89,1 %) avaient un RCV faible, 32 (10,8 %) un RCV élevé. Les principaux déterminants du RCV étaient : âge ≥ 50 ans (ORa 5), taux bas de HDL-c (ORa 4), taux élevé de LDL-c (ORa 6) et/ou de triglycéride (ORa 4) et l'appartenance au 3ème tertile de PCSK9 (ORa 4). Conclusion: Le taux plasmatique élevé de PCSK9 constitue un facteur de risque un RCV élevé dans cette population en bonne santé apparente. L’extension de l’étude dans la pulation générale est nécessaire pour la validation de ces résultats.

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Shim, Ye Jee, Jung-Sook Ha, Young-Rok Do, and Heung Sik Kim. "Whole-Exome Sequencing in Korean Children with Acute Lymphoblastic Leukemia." Blood 126, no. 23 (December 3, 2015): 4994. http://dx.doi.org/10.1182/blood.v126.23.4994.4994.

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Abstract Purpose: Next-generation sequencing methods recently have been applied for leukemia patients to discover genetic variants. In this study, we conducted whole-exome sequencing (WES) in Korean acute lymphoblastic leukemia (ALL) children to identify putative genetic drivers of leukemia. Methods: Four Korean ALL children were included for WES. For two of them, we also conducted WES after remission, considered as germline control. The characteristics of subjects and the diagnostic information are described in Table 1. Genomic DNA was extracted from the subject¡¯s bone marrow aspirates at diagnosis of leukemia and/or after remission. Whole-exome was captured by SureSelect Human All Exon V4 (Agilent Technologies, California, USA). Sequencing was performed using HiSeq2000 (Illumina, California, USA). Variants in dbSNP135 and TIARA database were excluded. Variants with minor allele frequencies > 0.5% of 1000g were filtered out. Functional variants (gain of stop codon, frameshifts and nonsynonymous SNVs) were selected as pathogenic mutations and were scanned for the 571 cancer gene set using ¡°Cancer gene Census¡± in COSMIC website. The finally selected variants were verified by PROVEAN, SIFT and PolyPhen-2. This research was approved by The Institutional Review Board in Keimyung University Dongsan Medical Center (Approval No., 2015-05-029-002). Results: After comparison between WES at diagnosis and WES after remission, p.W112C in PAX5 in patient 1 andp.G315C in KMT2C, p.T311P in NOTCH1, p.G11A in HOXD13 in patient 2 were considered as pathogenic, respectively. In patient 3 and 4, p.R293C in FNBP1, p.R254H in PCSK7, p.E11Q in TP53, p.R806Q in MYO5A, p.R108G in PPFIBP1, p.C1785R in RNF213, and p.A963P in WRN were suspected as putative drivers of leukemia. The respective variants are shown in Table 2. Conclusions: This is the first attempt of WES in Korean children with leukemia. WES is a valuable method to identify genomics of childhood ALL. Table 1. Characteristics and diagnostic information of four Korean acute lymphoblastic leukemia children. No. Diagnosis BMblast Karyotype Hemavision FISH Immunophenotype WESAt diagnosis WESAfter remission 1 B-ALL 88.4% 44,XX,der(2)t(2;?),-4,-9,der(9)t(2;9),der(16)t(9;16)(q13;q12) Negative . CD10, D19, CD20, CD22, cCD22,cCD79a, CD34, CD45 Yes Yes 2 Pre B-ALL 95.0% No mitosis t(1;19)(q23;p13) . CD38, CD138, CD10, CD19, CD22,cCD79a, HLA-DR, CD45 Yes Yes 3 B-ALL 88.6% 46,XX Negative . CD10, CD19, CD22, cCD79a, CD34,TdT, HLA-DR, CD45, CD38 Yes No 4 B-ALL 94.3% Hypotriploidywith structural abnormality/46,XY Negative Trisomy 5, 11, 12Tetrasomy 21 CD10, CD19, CD22, cCD79a, CD34,TdT, HLA-DR Yes No Table 2. Identified putative genetic drivers in four Korean acute lymphoblastic leukemia children by whole-exome sequencing. No. Gene Chr:Position Variant PROVEAN (score) SIFT (score) Polyphen-2 (score) Germline or somatic 1 PAX5 9:37015068 exon3:c.G336T:p.W112C Deleterious (-11.12) Damaging (0.000) Probably damaging (0.998) Somatic 2 KMT2C 7:151970859 exon7:c.G943T:p.G315C Deleterious (-7.05) Damaging (0.001) Probably damaging (1.000) Somatic NOTCH1 9:139413211 exon6:c.A931C:p.T311P Deleterious (-4.82) Damaging (0.012) Benign (0.033) Somatic HOXD13 2:176957650 exon1:c.G32C:p.G11A Neutral (-0.88) Tolerated (0.118) Possibly damaging (0.953) Somatic 3 FNBP1 9:132687349 exon9:c.C877T:p.R293C Deleterious (-6.03) Damaging (0.001) Probably damaging (1.000) Somatic PCSK7 11:117097881 exon5:c.G761A:p.R254H Deleterious (-3.30) Damaging (0.007) Probably damaging (0.991) Somatic 4 TP53 17:7579882 exon2:c.G31C:p.E11Q Neutral (0.42) Damaging (0.000) Probably damaging (0.996) Germline/somatic MYO5A 15:52668547 exon19:c.G2417A:p.R806Q Deleterious (-3.12) Damaging (0.003) Possibly damaging (0.575) Somatic PPFIBP1 12:27799046 exon5:c.C322G:p.R108G Deleterious (-5.76) Damaging (0.000) Probably damaging (1.000) Somatic RNF213 17:78313373 exon27:c.T5353C:p.C1785R Deleterious (-10.45) Damaging (0.000) Probably damaging (1.000) Somatic WRN 8:30989942 exon24:c.G2887C:p.A963P Deleterious (-3.90) Damaging (0.003) Probably damaging (0.988) Germline Disclosures No relevant conflicts of interest to declare.

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Mok, C. C., K. L. Chan, L. Y. Ho, S. M. Tse, and C. H. To. "POS0115 SERUM PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) AND CARDIOVASCULAR RISK IN SYSTEMIC LUPUS ERYTHEMATOSUS: A LONGITUDINAL COHORT STUDY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 282.1–283. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1441.

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ObjectivesTo study the effect of serum PCSK9 on major cardiovascular adverse events (MACEs) in Chinese patients with systemic lupus erythematosus (SLE).MethodsConsecutive patients who fulfilled ≥4 1997 ACR criteria for SLE and consented for a biomarker study between 2009 and 2012 were included. Stored serum samples from these patients were assayed for the levels of PCSK9 using a commercial ELISA kit (OKBB00903, Lot# 1344, Aviva Systems Biology, San Diego, US). New MACEs (acute coronary syndrome, ischemic stroke, peripheral vascular disease) documented by imaging and angiographic studies over time was evaluated. Patients were stratified into high/low PCSK9 groups according to the best cut-off level by ROC analysis for the prediction of these events. The cumulative incidence of new MACEs and mortality over time was studied by Kaplan-Meier’s analysis and compared between the high and low PCSK9 subgroups. Cox regression was performed to study the effect of the PCSK9 subgroups on new MACEs and mortality, adjusted for other confounding factors.Results539 SLE patients were studied (93% women, age 41.9±14.0 years; disease duration 106±90.4 months at entry). The mean PCSK level at baseline was 265±158ng/ml and a cut-off of 243.25ng/ml best predicted a new vascular event by the maximum Youden’s index (ROC analysis: AUC 0.63[0.51-0.74]; sensitivity 69%; specificity 61%). 220 SLE patients had baseline PCSK9 level of ≥243.25ng/ml (high PCSK9) and 319 patients had level below 243.25ng/ml (low PCSK9). Patients with high PCSK9 (n=220) had more active SLE than those with low PCSK9 (n=319) (p<0.001). PCSK9 level was highest in active renal SLE patients and correlated with SLE disease activity index (r=0.55; p<0.001). No significant difference in SLE manifestations and autoantibody profile was observed between the high and low PCSK9 groups except the former had a significantly higher prevalence of lupus nephritis. Over 91.3±18.6 months, 31 new MACEs (13 ischemic stroke, 13 acute coronary syndrome and 5 peripheral vascular disease) developed in 29 patients. Patients with a new MACE had a significantly higher baseline PCSK9 level than those without (350±225 vs 260±153ng.ml; p=0.02). The cumulative incidence of a first MACE at 5 years from study entry was 7.8% in the high PCSK9 group and 1.9% in the low PCSK9 group (log rank test; p=0.003, univariate hazard ratio [HR] 3.08[1.39-6.80]). At last follow-up, 40 patients succumbed (10 due to vascular event [vascular death]). Kaplan-Meier’s analysis showed that the high PCSK9 group had a significant higher cumulative risk of all-cause mortality (log rank test p=0.003; HR2.68[1.39-5.14]) and vascular mortality (log rank test p=0.002; HR12.4[1.56-98.4]) over time than the low PCSK9 group. Cox regression analyses showed that high PCSK9 was significantly associated with new MACEs (HR2.74[1.16-6.52]; p=0.02) independent of age, sex, SLE duration, history of nephritis, traditional atherosclerotic risk factors, antiphospholipid antibody, past history of vascular events, and the use of statins, aspirin/warfarin and immunosuppressive drugs (hydroxychloroquine, prednisolone, mycophenolate mofetil, azathioprine and the calcineurin inhibitors) at baseline. High PCSK9 was also independently associated with all-cause (HR2.55[1.27-5.12]; p=0.008) and vascular mortality (HR13.0[1.49-114]; p=0.02).ConclusionHigh circulating levels of PCSK9 increase the risk of MACEs and vascular mortality in patients with SLE.Disclosure of InterestsNone declared

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Morash, Michael G., Angela B. MacDonald, Roger P. Croll, and Younes Anini. "Molecular cloning, ontogeny and tissue distribution of zebrafish (Danio rerio) prohormone convertases: pcsk1 and pcsk2." General and Comparative Endocrinology 162, no. 2 (June 2009): 179–87. http://dx.doi.org/10.1016/j.ygcen.2009.03.013.

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Waseem, Tayab, William Coles Keeter, Alina Moriarty, Stefan Edemobi, Michael Pham, Andrew Getahun, John C. Cambier, and Elena Galkina. "B cell anergy: Atheroprotective, yet vulnerable to atherosclerotic conditions." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 121.14. http://dx.doi.org/10.4049/jimmunol.202.supp.121.14.

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Abstract Anergy is the major mechanism for peripheral tolerance. Recent reports highlight the role of B cell anergy in lupus, type 1 diabetes, and arthritis, but little is known about the induction and maintenance of anergic B cells within atherosclerosis. ARS/A1 mice have B cells that respond with moderate affinity to Ars hapten, but also cross-react with low affinity to endogenous ssDNA resulting in an anergic B cell repertoire. To explore the role of B cell anergy in atherosclerosis, we examine ARS/A1 and BL/6 littermate controls that have been fed a western diet for 16 weeks and injected with AAV-PCSK9 to induce atherosclerosis. Our data showed that ARS/A1 mice had 44% less lesions, and a decreased inflammatory profile compared to BL/6 controls. The role of B cells in atherosclerosis varies by B cell subsets. Whereas marginal zone B cells (MZ) are atheroprotective, follicular B cells (FO) accelerate atherosclerosis. To further explore how an atherosclerotic environment affects B cell subsets, we compared the percentages of splenic B cell subtypes in PCSK9-treated vs healthy ARS/A1 controls. Our data showed a significant decrease in ARS/A1 FO B cells and an increase in ARS/A1 MZ B cells suggesting a skewing of B cell subsets upon exposure to atherosclerotic conditions in ARS/A1 mice. Surprisingly, we detected an increased calcium response upon BCR crosslinking and increase levels of CD86 in B cells from PCSKS-9-injected ARS/A1 vs BL/6 controls. Overall, our data suggests that while anergy is atheroprotective, the inflammatory environment seen within atherosclerosis may prime B cells to increase the responsiveness of anergic B cells to activation.

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Garçon, Damien, François Moreau, Audrey Ayer, Wieneke Dijk, Xavier Prieur, Lucie Arnaud, Anna Roubtsova, et al. "Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 9 (September 2020): 2084–94. http://dx.doi.org/10.1161/atvbaha.120.314194.

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Objective: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9 -deficient (i- Pcsk9 −/− ) mouse model. PPL was measured in i- Pcsk9 −/− as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9 −/− mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr −/− mice. In contrast, i- Pcsk9 −/− mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9 +/+ but not in Pcsk9 −/− mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9 +/+ mice. Conclusions: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.

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Chrétien, Michel, and Majambu Mbikay. "60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9)." Journal of Molecular Endocrinology 56, no. 4 (May 2016): T49—T62. http://dx.doi.org/10.1530/jme-15-0261.

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Pro-opiomelanocortin (POMC), is a polyprotein expressed in the pituitary and the brain where it is proteolytically processed into peptide hormones and neuropeptides with distinct biological activities. It is the prototype of multipotent prohormones. The prohormone theory was first suggested in 1967 when Chrétien and Li discovered γ-lipotropin and observed that (i) it was part of β-lipotropin (β-LPH), a larger polypeptide characterized 2 years earlier and (ii) its C-terminus was β-melanocyte-stimulating hormone (β-MSH). This discovery led them to propose that the lipotropins might be related biosynthetically to the biologically active β-MSH in a precursor to end product relationship. The theory was widely confirmed in subsequent years. As we celebrate the 50th anniversary of the sequencing of β-LPH, we reflect over the lessons learned from the sequencing of those proteins; we explain their extension to the larger POMC precursor; we examine how the theory of precursor endoproteolysis they inspired became relevant for vast fields in biology; and how it led, after a long and arduous search, to the novel proteolytic enzymes called proprotein convertases. This family of nine enzymes plays multifaceted functions in growth, development, metabolism, endocrine, and brain functions. Their genetics has provided many insights into health and disease. Their therapeutic targeting is foreseeable in the near future. Thus, what started five decades ago as a theory based on POMC fragments, has opened up novel and productive avenues of biological and medical research, including, for our own current interest, a highly intriguing hypocholesterolemic Gln152His PCSK9 mutation in French-Canadian families.

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Di Minno, Alessandro, Roberta Clara Orsini, Mattia Chiesa, Viviana Cavalca, Ilenia Calcaterra, Maria Tripaldella, Andrea Anesi, et al. "Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach." Biomedicines 9, no. 8 (August 23, 2021): 1073. http://dx.doi.org/10.3390/biomedicines9081073.

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Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

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Mayne, Janice, Thilina Dewpura, Angela Raymond, Lise Bernier, Marion Cousins, Teik Chye Ooi, Jean Davignon, Nabil G. Seidah, Majambu Mbikay, and Michel Chrétien. "Novel Loss-of-Function PCSK9 Variant Is Associated with Low Plasma LDL Cholesterol in a French-Canadian Family and with Impaired Processing and Secretion in Cell Culture." Clinical Chemistry 57, no. 10 (October 1, 2011): 1415–23. http://dx.doi.org/10.1373/clinchem.2011.165191.

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BACKGROUND PCSK9 (proprotein convertase subtilisin/kexin type 9) is a polymorphic gene whose protein product regulates plasma LDL cholesterol (LDLC) concentrations by shuttling liver LDL receptors (LDLRs) for degradation. PCSK9 variants that cause a gain or loss of PCSK9 function are associated with hyper- or hypocholesterolemia, which increases or reduces the risk of cardiovascular disease, respectively. We studied the clinical and molecular characteristics of a novel PCSK9 loss-of-function sequence variant in a white French-Canadian family. METHODS In vivo plasma and ex vivo secreted PCSK9 concentrations were measured with a commercial ELISA. We sequenced the PCSK9 exons for 15 members of a family, the proband of which exhibited very low plasma PCSK9 and LDLC concentrations. We then conducted a structure/function analysis of the novel PCSK9 variant in cell culture to identify its phenotypic basis. RESULTS We identified a PCSK9 sequence variant in the French-Canadian family that produced the PCSK9 Q152H substitution. Family members carrying this variant had mean decreases in circulating PCSK9 and LDLC concentrations of 79% and 48%, respectively, compared with unrelated noncarriers (n=210). In cell culture, the proPCSK9-Q152H variant did not undergo efficient autocatalytic cleavage and was not secreted. Cells transiently transfected with PCSK9-Q152H cDNA had LDLR concentrations that were significantly higher than those of cells overproducing wild-type PCSK9 (PCSK9-WT). Cotransfection of PCSK9-Q152H and PCSK9-WT cDNAs produced a 78% decrease in the secreted PCSK9-WT protein compared with control cells. CONCLUSIONS Collectively, our results demonstrate that the PCSK9-Q152H variant markedly lowers plasma PCSK9 and LDLC concentrations in heterozygous carriers via decreased autocatalytic processing and secretion, and hence, inactivity on the LDLR.

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Goksøyr, Louise, Magdalena Skrzypczak, Maureen Sampson, Morten A. Nielsen, Ali Salanti, Thor G. Theander, Alan T. Remaley, Willem A. De Jongh, and Adam F. Sander. "A cVLP-Based Vaccine Displaying Full-Length PCSK9 Elicits a Higher Reduction in Plasma PCSK9 Than Similar Peptide-Based cVLP Vaccines." Vaccines 11, no. 1 (December 20, 2022): 2. http://dx.doi.org/10.3390/vaccines11010002.

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Administration of PCSK9-specific monoclonal antibodies, as well as peptide-based PCSK9 vaccines, can lower plasma LDL cholesterol by blocking PCSK9. However, these treatments also cause an increase in plasma PCSK9 levels, presumably due to the formation of immune complexes. Here, we utilize a versatile capsid virus-like particle (cVLP)-based vaccine platform to deliver both full-length (FL) PCSK9 and PCSK9-derived peptide antigens, to investigate whether induction of a broader polyclonal anti-PCSK9 antibody response would mediate more efficient clearance of plasma PCSK9. This head-to-head immunization study reveals a significantly increased capacity of the FL PCSK9 cVLP vaccine to opsonize and clear plasma PCSK9. These findings may have implications for the design of PCSK9 and other vaccines that should effectively mediate opsonization and immune clearance of target antigens.

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Vohnout, Branislav, Jana Lisičanová, and Andrea Havranová. "PCSK9 inhibitors and diabetes mellitus." Vnitřní lékařství 64, no. 12 (December 1, 2018): 1186–89. http://dx.doi.org/10.36290/vnl.2018.170.

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Chen, Po-Wei, Shih-Ya Tseng, Hsien-Yuan Chang, Cheng-Han Lee, and Ting-Hsing Chao. "Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9 between Obesity and Non-Obesity." International Journal of Molecular Sciences 23, no. 17 (August 29, 2022): 9768. http://dx.doi.org/10.3390/ijms23179768.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported. Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis. We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vitro, cilostazol treatment increased PCSK9 expression in vehicle-treated HepG2 cells but decreased PCSK9 expression in palmitic acid-treated HepG2 cells. In vivo, cilostazol treatment increased the serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice. The expressions of PCSK9-relevant microRNAs also showed similar results. Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrates the therapeutic potential of cilostazol in clinical settings.

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Bordicchia, Marica, Francesco Spannella, Gianna Ferretti, Tiziana Bacchetti, Arianna Vignini, Chiara Di Pentima, Laura Mazzanti, and Riccardo Sarzani. "PCSK9 is Expressed in Human Visceral Adipose Tissue and Regulated by Insulin and Cardiac Natriuretic Peptides." International Journal of Molecular Sciences 20, no. 2 (January 9, 2019): 245. http://dx.doi.org/10.3390/ijms20020245.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein receptor (LDLR), contributing to hypercholesterolemia. Adipose tissue plays a role in lipoprotein metabolism, but there are almost no data about PCSK9 and LDLR regulation in human adipocytes. We studied PCSK9 and LDLR regulation by insulin, atrial natriuretic peptide (ANP, a potent lipolytic agonist that antagonizes insulin), and LDL in visceral adipose tissue (VAT) and in human cultured adipocytes. PCSK9 was expressed in VAT and its expression was positively correlated with body mass index (BMI). Both intracellular mature and secreted PCSK9 were abundant in cultured human adipocytes. Insulin induced PCSK9, LDLR, and sterol-regulatory element-binding protein-1c (SREBP-1c) and -2 expression (SREBP-2). ANP reduced insulin-induced PCSK9, especially in the context of a medium simulating hyperglycemia. Human LDL induced both mature and secreted PCSK9 and reduced LDLR. ANP indirectly blocked the LDLR degradation, reducing the positive effect of LDL on PCSK9. In conclusion, PCSK9 is expressed in human adipocytes. When the expression of PCSK9 is induced, LDLR is reduced through the PCSK9-mediated degradation. On the contrary, when the induction of PCSK9 by insulin and LDL is partially blocked by ANP, the LDLR degradation is reduced. This suggests that NPs could be able to control LDLR levels, preventing PCSK9 overexpression.

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Petersen-Uribe, Álvaro, Marcel Kremser, Anne-Katrin Rohlfing, Tatsiana Castor, Kyra Kolb, Valerie Dicenta, Frederic Emschermann, et al. "Platelet-Derived PCSK9 Is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease." International Journal of Molecular Sciences 22, no. 20 (October 16, 2021): 11179. http://dx.doi.org/10.3390/ijms222011179.

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Platelets play a significant role in atherothrombosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of LDL metabolism and interacts with platelet function. The effect of PCSK9 in platelet function is poorly understood. The authors of this article sought to characterize platelets as a major source of PCSK9 and PCSK9’s role in atherothrombosis. In a large cohort of patients with coronary artery disease (CAD), platelet count, platelet reactivity, and platelet-derived PCSK9 release were analyzed. The role of platelet PCSK9 on platelet and monocyte function was investigated in vitro. Platelet count and hyper-reactivity correlated with plasma LDL in CAD. The circulating platelets express on their surface and release substantial amounts of PCSK9. Release of PCSK9 augmented platelet-dependent thrombosis, monocyte migration, and differentiation into macrophages/foam cells. Platelets and PCSK9 accumulated in tissue derived from atherosclerotic carotid arteries in areas of macrophages. PCSK9 inhibition reduced platelet activation and platelet-dependent thrombo-inflammation. The authors identified platelets as a source of PCSK9 in CAD, which may have an impact on LDL metabolism. Furthermore, platelet-derived PCSK9 contributes to atherothrombosis, and inhibition of PCSK9 attenuates thrombo-inflammation, which may contribute to the reported beneficial clinical effects.

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Toscano, Arianna, Maria Cinquegrani, Michele Scuruchi, Antonino Di Pino, Salvatore Piro, Viviana Ferrara, Carmela Morace, et al. "PCSK9 Plasma Levels Are Associated with Mechanical Vascular Impairment in Familial Hypercholesterolemia Subjects without a History of Atherosclerotic Cardiovascular Disease: Results of Six-Month Add-On PCSK9 Inhibitor Therapy." Biomolecules 12, no. 4 (April 9, 2022): 562. http://dx.doi.org/10.3390/biom12040562.

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Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the role of PCSK9 in vascular damage. We aimed to evaluate the impact of PCSK9 plasma levels on pulse wave velocity (PWV) and the effect of PCSK9 inhibitors (PCSK9-i) on circulating PCSK9 and PWV in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. In a previous step, HeFH patients were enrolled and LLT was prescribed according to guidelines. Biochemical analyses and PWV assessment were performed at baseline (T0), after 6 months of high-efficacy statin plus ezetimibe (T1) and after 6 months of PCSK9-i (T2). The PCSK9 levels were evaluated in 26 selected HeFH subjects at the three time points and 26 healthy subjects served as controls for the reference value for PCSK9 plasma levels. The PWV values decreased at each time point in HeFH subjects after LLT starting (8.61 ± 2.4 m/s, −8.7%; p < 0.001 vs. baseline at T1, and 7.9 ± 2.1 m/s, −9.3%; p < 0.001 vs. both T1 and baseline) and it was correlated to PCSK9 (r = 0.411, p = 0.03). The PCSK9 levels increased on statin/EZE therapy (+42.8% at T1) while it decreased after PCSK9-i was started (−34.4% at T2). We noted a significant relationship between PCSK9 levels and PWV changes at T1 and T2. In conclusion, PCSK9 levels were associated with baseline PWV values in HeFH subjects; moreover, we found that PCSK9 level variations seemed to be correlated with PWV changes on LLT. A longer observation time and wider sample size are needed to assess the potential role of PCSK9 plasma levels on the vascular function and remodelling, and to clarify the effects of PCSK9-i in these pathways.

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Sobati, Saeideh, Amir Shakouri, Mahdi Edalati, Daryoush Mohammadnejad, Reza Parvan, Javad Masoumi, and Jalal Abdolalizadeh. "PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD)." Advanced Pharmaceutical Bulletin 10, no. 4 (August 9, 2020): 502–11. http://dx.doi.org/10.34172/apb.2020.062.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-densitylipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it bindsto LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growthfactor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLRexpression is adjusted at the transcriptional level through sterol regulatory element bindingprotein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and theinducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing theconcentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, theeffect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniquesthat focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 havebeen proposed which concentrate on both extracellular and intracellular PCSK9, and theyinclude blockage of PCSK9 production by using gene silencing agents and blockage of it’sbinding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tinymolecule inhibitors.

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Guo, Yanan, Zhihan Tang, Binjie Yan, Hao Yin, Shi Tai, Juan Peng, Yuting Cui, et al. "PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Triggers Vascular Smooth Muscle Cell Senescence and Apoptosis: Implication of Its Direct Role in Degenerative Vascular Disease." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 1 (January 2022): 67–86. http://dx.doi.org/10.1161/atvbaha.121.316902.

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Objective: PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9–LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of Pcsk9 accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the “shoulder” regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin. Conclusions: Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.

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Duff, Christopher J., Martin J. Scott, Ian T. Kirby, Sue E. Hutchinson, Steve L. Martin, and Nigel M. Hooper. "Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor." Biochemical Journal 419, no. 3 (April 14, 2009): 577–84. http://dx.doi.org/10.1042/bj20082407.

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PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes degradation of the LDLR [LDL (low-density lipoprotein) receptor] through an as-yet-undefined mechanism, leading to a reduction in cellular LDLc (LDL-cholesterol) and a concomitant increase in serum LDLc. Central to the function of PCSK9 is a direct protein–protein interaction formed with the LDLR. In the present study, we investigated a strategy to modulate LDL uptake by blocking this interaction using specific antibodies directed against PCSK9. Studies using surface plasmon resonance demonstrated that direct binding of PCSK9 to the LDLR could be abolished with three different anti-PCSK9 antibodies. Two of these antibodies were raised against peptide epitopes in a region of the catalytic domain of PCSK9 that is involved in the interaction with the LDLR. Such antibodies restored LDL uptake in HepG2 cells treated with exogenous PCSK9 and in HepG2 cells engineered to overexpress recombinant PCSK9. This latter observation indicates that antibodies blocking the PCSK9–LDLR interaction can inhibit the action of PCSK9 produced endogenously in a cell-based system. These antibodies also disrupted the higher-affinity interaction between the natural gain-of-function mutant of PCSK9, D374Y, and the LDLR in both the cell-free and cell-based assays. These data indicate that antibodies targeting PCSK9 can reverse the PCSK9-mediated modulation of cell-surface LDLRs.

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Wang, Feifei, Min Li, Aidong Zhang, Hairui Li, Can Jiang, and Jun Guo. "PCSK9 Modulates Macrophage Polarization-Mediated Ventricular Remodeling after Myocardial Infarction." Journal of Immunology Research 2022 (July 4, 2022): 1–18. http://dx.doi.org/10.1155/2022/7685796.

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Background and Aims. An increasing number of high-risk patients with coronary heart disease (similar to acute myocardial infarction (AMI)) are using PCSK9 inhibitors. However, whether PCSK9 affects myocardial repair and the molecular mechanism of PCSK9 modulation of immune inflammation after AMI are not known. The present research investigated the role of PCSK9 in the immunomodulation of macrophages after AMI and provided evidence for the clinical application of PCSK9 inhibitors after AMI to improve cardiac repair. Methods and Results. Wild-type C57BL6/J (WT) and PCSK9-/- mouse hearts were subjected to left anterior descending (LAD) coronary artery occlusion to establish an AMI model. Correlation analysis showed that higher PCSK9 expression indicated worse cardiac function after AMI, and PCSK9 knockout reduced infarct size, improved cardiac function, and attenuated inflammatory cell infiltration compared to WT mice. Notably, the curative effects of PCSK9 inhibition were abolished after the systemic depletion of macrophages using clodronate liposomes. PCSK9 showed a regulatory effect on macrophage polarization in vivo and in vitro. Our studies also revealed that activation of the TLR4/MyD88/NF-κB axis was a possible mechanism of PCSK9 regulation of macrophage polarization. Conclusion. Our data suggested that PCSK9 modulated macrophage polarization-mediated ventricular remodeling after myocardial infarction.

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Da Dalt, Lorenzo, Laura Castiglioni, Andrea Baragetti, Matteo Audano, Monika Svecla, Fabrizia Bonacina, Silvia Pedretti, et al. "PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction." European Heart Journal 42, no. 32 (July 12, 2021): 3078–90. http://dx.doi.org/10.1093/eurheartj/ehab431.

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Abstract Aims PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function. Methods and results Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects. Conclusion PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF.

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Larrea-Sebal, Asier, Chiara Trenti, Shifa Jebari-Benslaiman, Stefano Bertolini, Sebastiano Calandra, Emanuele A. Negri, Efrem Bonelli, et al. "Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject." International Journal of Molecular Sciences 24, no. 4 (February 7, 2023): 3330. http://dx.doi.org/10.3390/ijms24043330.

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Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that led to reduced plasma LDL-C clearance. To date, several PCSK9 gain-of-function (GOF) variants causing FH have been described based on their increased ability to degrade LDLr. On the other hand, mutations that reduce the activity of PCSK9 on LDLr degradation have been described as loss-of-function (LOF) variants. It is therefore important to functionally characterise PCSK9 variants in order to support the genetic diagnosis of FH. The aim of this work is to functionally characterise the p.(Arg160Gln) PCSK9 variant found in a subject suspected to have FH. Different techniques have been combined to determine efficiency of the autocatalytic cleavage, protein expression, effect of the variant on LDLr activity and affinity of the PCSK9 variant for the LDLr. Expression and processing of the p.(Arg160Gln) variant had a result similar to that of WT PCSK9. The effect of p.(Arg160Gln) PCSK9 on LDLr activity is lower than WT PCSK9, with higher values of LDL internalisation (13%) and p.(Arg160Gln) PCSK9 affinity for the LDLr is lower than WT, EC50 8.6 ± 0.8 and 25.9 ± 0.7, respectively. The p.(Arg160Gln) PCSK9 variant is a LOF PCSK9 whose loss of activity is caused by a displacement of the PCSK9 P’ helix, which reduces the stability of the LDLr-PCSK9 complex.

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Shapiro, Michael D., Hagai Tavori, and Sergio Fazio. "PCSK9." Circulation Research 122, no. 10 (May 11, 2018): 1420–38. http://dx.doi.org/10.1161/circresaha.118.311227.

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Seidah, Nabil G., Zuhier Awan, Michel Chrétien, and Majambu Mbikay. "PCSK9." Circulation Research 114, no. 6 (March 14, 2014): 1022–36. http://dx.doi.org/10.1161/circresaha.114.301621.

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Zheng, Xiaoya, Wei Ren, Suhua Zhang, Jingjing Liu, Sufang Li, Jinchao Li, Ping Yang, Jun He, Shaochu Su, and Ping Li. "Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and PCSK2) and proinsulin conversion in a Chinese population." Molecular Biology Reports 39, no. 1 (March 25, 2011): 17–23. http://dx.doi.org/10.1007/s11033-011-0705-6.

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McKenney, James M. "Understanding PCSK9 and anti-PCSK9 therapies." Journal of Clinical Lipidology 9, no. 2 (March 2015): 170–86. http://dx.doi.org/10.1016/j.jacl.2015.01.001.

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Ding, Zufeng, Naga Venkata K. Pothineni, Akshay Goel, Thomas F. Lüscher, and Jawahar L. Mehta. "PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1." Cardiovascular Research 116, no. 5 (November 20, 2019): 908–15. http://dx.doi.org/10.1093/cvr/cvz313.

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Abstract PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

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Grimm, Jonathan, Georg Peschel, Martina Müller, Doris Schacherer, Reiner Wiest, Kilian Weigand, and Christa Buechler. "Rapid Decline of Serum Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) in Non-Cirrhotic Patients with Chronic Hepatitis C Infection Receiving Direct-Acting Antiviral Therapy." Journal of Clinical Medicine 10, no. 8 (April 11, 2021): 1621. http://dx.doi.org/10.3390/jcm10081621.

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Direct-acting antivirals (DAAs) efficiently eradicate the hepatitis C virus (HCV). Low-density lipoprotein (LDL) levels increase rapidly upon DAA treatment. Proprotein convertase subtilisin/kexin 9 (PCSK9) induces degradation of the hepatic LDL receptor and thereby elevates serum LDL. The aim of this study was to determine serum PCSK9 concentrations during and after DAA therapy to identify associations with LDL levels. Serum PCSK9 was increased in 82 chronic HCV-infected patients compared to 55 patients not infected with HCV. Serum PCSK9 was low in HCV patients with liver cirrhosis, but patients with HCV-induced liver cirrhosis still exhibited higher serum PCSK9 than patients with non-viral liver cirrhosis. Serum PCSK9 correlated with measures of liver injury and inflammation in cirrhotic HCV patients. In patients without liver cirrhosis, a positive association of serum PCSK9 with viral load existed. Serum PCSK9 was not different between viral genotypes. Serum PCSK9 did not correlate with LDL levels in HCV patients irrespective of cirrhotic status. Serum PCSK9 was reduced, and LDL was increased at four weeks after DAA therapy start in non-cirrhotic HCV patients. Serum PCSK9 and LDL did not change upon DAA treatment in the cirrhotic group. The rapid decline of PCSK9 after the start of DAA therapy in conjunction with raised LDL levels in non-cirrhotic HCV patients shows that these changes are not functionally related.

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