Relevant bibliographies by topics / PCSK7

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Academic literature on the topic 'PCSK7'

Author: Grafiati
Published: 9 March 2023
Last updated: 10 March 2023

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Journal articles on the topic "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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Dissertations / Theses on the topic "PCSK7"

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GRENI, FEDERICO. "Variabilità fenotipica nell'emocromatosi: studio di due potenziali modificatori genetici in PCSK7 e GNPAT." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/140994.

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Introduction and aim: Hereditary hemochromatosis (HH) is a genetic disease characterized by a progressive iron overload in different tissues. Homozygosity for the p.C282Y mutation is the most frequent genotype associated with the disease and it is directly responsible for an inappropriate production of hepcidin, the main regulator of iron homeostasis. Several evidences indicated that p.C282Y homozygous genotype has an incomplete penetrance due to the combined action of genetic and acquired modifier factors. Recently, the attention was focused on GNPAT rs11558492 and PCSK7 rs236918 single nucleotide polymorphisms (SNPs). The aim of my thesis was to analyse the role of these potential genetic modifiers in an Italian cohort of p.C282Y homozygotes. Materials and methods: Patients: 298 patients (205 males and 93 females) and 169 healthy controls. Exclusion criteria were: alcohol intake >50 g/day in men and >30 g/day in women, chronic hepatitis, inflammatory status. SNPs genotyping was performed by ARMS-PCR or PCR-RFLP. Random samples were confirmed by direct sequencing. Patients and controls allelic and genotypic frequencies were compared to EVS database and analysed according to serum ferritin levels (SF), liver iron concentration (LIC) measured by liver biopsy or magnetic resonance, iron removed (IR) and liver fibrosis histologically assessed by Ishak score (IS). Fisher’s exact test, chi-squared test and t-test were used to perform statistical comparisons between groups and averages of considered variables. Results: GNPAT rs11558492 analysis. Our results demonstrated that: a. allelic and genotypic frequencies were comparable among patients, controls and EVS data. No significant differences were found even considering two subgroups of males only with extreme phenotypes (SF <1000 mcg/L, IR <5 g and/or LIC <100 mcmol/g vs SF >2000 mcg/L, IR >10 g and/or LIC> 50 mcmol/g); b. according to iron indices, allelic and genotypic frequencies did not significantly differ neither among patients nor compared to controls, limited to SF; c. similarly, minor allele (G) frequency did not differ between patients with absent/mild fibrosis and patients with severe fibrosis/cirrhosis (20.5% vs 25%). PCSK7 rs236918 analysis. Our study demonstrated that: a. minor allele (C) frequency was higher in patients with severe fibrosis/cirrhosis than in patients with absent/mild fibrosis (21.9% vs 7.1%; p=0.003); b. C-allele carriers were more likely to have worse liver staging scores than wild-type patients (OR=2.77, p=0.0018; ORmale-only=2.56, p=0.0233); c. PCSK7 genotype has a direct effect on severe fibrosis/cirrhosis (OR=3.11, p=0.0157) and a mild nonsignificant indirect effect mediated through SF and IR (mediation analysis: 22% and 28%, respectively). Conclusions: Our results demonstrated that: a. GNPAT rs11558492 is not a major modifier of iron status in HH patients and controls, and is not associated with severe fibrosis/cirrhosis in HH patients. b. PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian HH patients.
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Bhat, Mamatha. "Expression of PCSK9 in Hepatocellular Carcinoma." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106271.

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Hepatocellular carcinoma (HCC) is an often fatal condition due to late diagnosis, resistance to existing anticancer agents, as well as underlying liver disease that can limit the use of hepatotoxic chemotherapy. Proprotein convertases (PCs) are serine proteases that convert a variety of growth factors, cell surface glycoproteins, receptors and metalloproteinases into their active forms, thus regulating the biological activity of these proteins. PCs have been found to be upregulated in various malignancies. Growth factors implicated in HCC, such as IGF-1, HGF, VEGF and PDGF, have all been shown to be converted into their active forms by PCs. In this study, I explored the hypothesis that expression of proprotein convertases, specifically PCSK9, furin and PC5, is elevated in HCC. This was evaluated through construction of a Tissue Microarray and staining for these proteins. We found that PCSK9 expression was significantly downregulated in HCC tumours associated with poorer survival. PCSK9 is upregulated in the context of liver regeneration and has been involved in cholesterol metabolism, with development of monoclonal antibodies against PCSK9 to treat hypercholesterolemia. Its altered expression in aggressive HCC tumours potentially indicates that HCC is able to modulate its local microenvironment to enable a constant energy supply. There has recently been a move in oncology research to study suppression of suppress tumour growth by modifying energy supply and metabolism (for eg, metformin in prostate and breast cancer). Further confirmation at the mRNA level is required to confirm the altered expression of PCSK9, however this appears to be a promising finding and potential chemotherapeutic target.
Contexte et hypothèses: Le carcinome hépatocellulaire (CHC) est le 5e cancer le plus courant dans le monde entier et la 3ème cause de décès par cancer dans le monde entier, avec une survie médiane à 5 ans de 8,9%. La reconnaissance tardive en raison du manque de biomarqueurs pour détecter la maladie résécable, une résistance aux agents anticancéreux, ainsi qu'une maladie du foie sous-jacente limitant l'utilisation de chimiothérapie hépatotoxique sont des facteurs qui diminuent le taux de survie. Les proprotéines convertases (PCs) sont des sérine-protéases qui convertissent une variété de facteurs de croissance, glycoprotéines de surface cellulaire, les récepteurs, et les métalloprotéinases à leurs formes actives, contrôlant ainsi l'activité biologique de ces protéines. On a démontré l'expression augmentée de PCs dans de diverses tumeurs malignes. On a prouvé que les facteurs de croissance impliqués dans le CHC, tels que l'IGF-1, HGF, VEGF et PDGF, sont convertis à leurs forme actives par les PC. Notre hypothèse est que l'expression de proprotéines convertases est élevée dans le CHC, permettant l'activation de différentes protéines essentielles dans le développement et la progression du CHC. L'objectif de recherche était d'évaluer l'expression des PCs PCSK9, furine et PC5 dans le CHC par rapport aux stroma environnant, zones péri-cirrhotiques, et foie normal afin de déterminer si un gradient d'expression existe. PCSK9 en particulier est connu comme étant plus exprimé chez le foie régénérateur post-hepatectomie. Les diapositives de pathologie de CHC stockés dans le département de pathologie du CUSM ont été examinés par une pathologiste, et les zones appropriées (tumeur de CHC, interface de tumeur et du foie, le foie cirrhotique, et d'autres échantillons d'hépatite et de foie normal) dans les blocs de tissu correspondants ont été creusés et ont été incorporées dans un microarray de tissu (TMA). Des lignes cellulaires de CHC etablies, dont le HepG2 et le Huh7, avec des profils d'expression de PC connus, ont été incorporées sous forme de pastilles de cellules dans la TMA, afin de servir de témoins positifs et négatifs. La TMA a été sectionnée en diapositives, qui ont été colorées avec des anticorps de la PCSK9, furine et PC5. On a découvert que le niveau d'expression de PCSK9 était diminuée dans les CHC avec un pire prognostique. L'expression augmentée de PCSK9 dans les CHC plus aggressifs pourrait indiquer un rôle du PCSK9 dans la tumorigenèse, directement ou indirectement. Il se peut que les CHCs plus aggressifs sont capables de modifier l'environnement local pour apprivoiser l'énergie métabolique, et que le PCSK9 permet que le cholestérol soit utilisé comme source d'énergie. La confirmation de son importance fonctionnelle avec mRNA pourrait potentiellement mener au développement de chimiothérapie ciblée avec des anticorps contre le PCSK9 (stratégie en étude pour l'hypercholestérolémie). Compte tenu des options chimiothérapeutiques actuellement limitées pour le CHC, une telle constatation pourrait améliorer la prise en charge clinique du CHC.
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DA, DALT LORENZO. "IMPACT OF PCSK9 ON EXTRAHEPATIC TISSUES." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/813080.

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Introduzione e scopo: la proproteina convertasi subtilisina kexin tipo 9 (PCSK9) è una glicoproteina di 692 amminoacidi che appartiene alla famiglia delle proproteine convertasi. È prodotta principalmente dal fegato dal quale viene secreta nel torrente circolatorio. PCSK9 interagisce con diversi recettori della famiglia dell’LDLr, inclusi VLDLr, LRP1 ma anche con CD36, e guida la loro degradazione lisosomiale. La mancanza di PCSK9 determina quindi una maggiore espressione dei recettori della famiglia LDLr e favorisce l'accumulo di lipidi nei tessuti extraepatici. L’eccesso di lipidi cellulari è associato a disfunzione mitocondriale e danni tissutali in diversi organi, tra cui il pancreas e il cuore. Per questo motivo ci siamo chiesti se la mancanza di PCSK9 circolante e localmente prodotto possa influenzare l'accumulo di lipidi nei tessuti extraepatici come il pancreas e il cuore influenzandone la funzionalità. Metodi: Animali WT, Pcsk9 KO, albumin CRE PCSK9LoxP / LoxP KO condizionali (privi di PCSK9 selettivamente nel fegato e quindi non presentando proteina PCSK9 rilevabile in circolazione) e topi maschi Doppi KO LDLr-Pcsk9 di 2 mesi sono stati nutriti per 20 settimane con SFD o HFD. I livelli plasmatici di GTT, ITT, insulina e peptide C, morfologia del pancreas e accumulo di colesterolo nelle isole pancreatiche sono stati studiati nei diversi modelli animali. Inoltre su questi topi sono state eseguite analisi ecocardiografiche del cuore e test funzionali. La respirazione mitocondriale è stata studiata in condizioni di riposo e in seguito a condizioni massime di accoppiamento e disaccoppiamento in tutti i modelli di topo, seguite da caratterizzazione delle proteine mitocondriali mediante western blot e analisi di metabolomica approfondita. Risultati: Il metabolismo glucidico è significativamente ridotto nei topi Pcsk9 KO alimentati sia con una dieta standard che con una dieta ricca di grassi per 20 settimane rispetto agli animali WT; la sensibilità all'insulina, tuttavia, non viene alterata. Un'analisi dettagliata della morfologia del pancreas dei topi Pcsk9 KO rispetto ai controlli ha rivelato isole più grandi con un maggiore accumulo di esteri del colesterolo, che si associa ad aumentati livelli intracellulari di insulina e alla diminuzione dei livelli plasmatici di insulina e C-peptide. Questo fenotipo è stato completamente ripristinato nei topi Pcsk9 / Ldlr DKO, il che implica che l’aumentata espressione di LDLr potrebbe spiegare il fenotipo osservato. Da notare che i topi privi di PCSK9 circolante non presentavano un fenotipo alterato, indicando così che PCSK9 circolante e di origine epatica non influisce sulla funzione delle cellule beta e sulla secrezione di insulina. In parallelo, una caratterizzazione dettagliata della funzionalità cardiaca, ha rivelato che i topi Pcsk9 KO mostrano un fenotipo caratteristico dello scompenso cardiaco con frazione di eiezione conservata. Inoltre, i topi Pcsk9 KO presentano una ridotta resistenza alla corsa senza difetti muscolari accoppiata a importanti adattamenti nel metabolismo cardiaco e nella funzionalità mitocondriale dovuti all'accumulo di colesterolo cardiaco. Un fenotipo simile è stato osservato negli LDLr Doppi KO confermando un effetto indipendente dall'espressione dell’LDLr. Il fenotipo cardiaco risulta completamente ristabilito nel modello KO selettivo del fegato escludendo così il coinvolgimento del PCSK9 circolante nello sviluppo dell'insufficienza cardiaca con frazione di eiezione conservata. Studi traslazionali hanno mostrato che i soggetti umani portatori del polimorfismo di perdita di funzione R46L mostravano un aumento della massa ventricolare sinistra senza alterazioni nella frazione di eiezione rispetto ai controlli con BMI R46R abbinati. Conclusione / Discussione: PCSK9 prodotto localmente nel pancreas e nel cuore limita l'accumulo di lipidi in modo dipendente da LDLr nel pancreas e in modo LDLr indipendente nel cuore contribuendo così a mantenere l'omeostasi dei tessuti. La carenza genetica di PCSK9 porta allo sviluppo di intolleranza al glucosio e insufficienza cardiaca con frazione di eiezione conservata nei modelli murini e nell'uomo.
Background and Aim: Proprotein convertase subtilisin Kexin type 9 (PCSK9) is a 692-amino acid glycoprotein that belongs to the family of proprotein convertases. It is produced mainly by the liver and secreted into the circulation. PCSK9 interacts with several receptors of the LDLr family, including VLDLr, LRP1 but also with CD36, and drives their degradation in the lysosome. As a consequence, PCSK9 deficiency results in increased expression of LDLr family receptors and favors lipid accumulation in extrahepatic tissues. Lipids overload is associated with mitochondrial dysfunction and tissue damage in different organs including the pancreas and the heart. We wondered whether the lack of both circulating and locally produced PCSK9 may affect lipid accumulation on extrahepatic tissues such as the pancreas and the heart those affecting their functionality. Methods: 2-months old WT, Pcsk9 KO, Albumin CRE PCSK9LoxP/LoxP conditional KO (lacking PCSK9 production selectively in the liver and thus presenting undetectable PCSK9 protein in the circulation) and Double KO LDLr-Pcsk9 male mice were fed for 20 weeks with SFD or HFD. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Moreover, echocardiographic analysis of the heart and functional tests were performed on these mice. Mitochondrial respiration was investigated under resting conditions and following maximal coupling and uncoupling conditions in all mice models followed by mitochondrial protein profiling by western blotting and extensive metabolomic analysis. Results: Glucose clearance was significantly reduced in Pcsk9 KO mice fed with a standard or a high-fat diet for 20 weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying that increased LDLR could explain the phenotype observed. Of note mice lacking circulating PCSK9 did not present an impaired phenotype, thus indicating that circulating, liver-derived PCSK9 does not impact beta-cell function and insulin secretion. In parallel, a detailed characterization of heart function revealed that Pcsk9 KO displays a phenotype characteristic of heart failure with preserved ejection fraction. Moreover, PCSK9 KO mice present a reduced running resistance without muscular defects coupled to major adaptations in cardiac metabolism and mitochondrial functionality due to heart cholesterol accumulation. A similar phenotype was observed in LDLr Double KO confirming an effect independent of LDLr expression. The cardiac phenotype is completed reverted in the liver selective KO model thus excluding the involvement of circulating PCSK9 in the development of Heart Failure with preserved Ejection Fraction. Translational studies showed that human subjects carrying the R46L loss of function polymorphism displayed increased left ventricular mass without alterations in ejection fraction compared to R46R BMI-matched controls. Conclusion/Discussion: PCSK9 locally produced in the pancreas and the heart affects limits lipid accumulation in an LDLr dependent manner in the pancreas and an LDLr independent manner in the heart thus contributing to maintaining tissue homeostasis. Genetic PCSK9 deficiency leads to the development of glucose intolerance and heart failure with preserved ejection fraction in mice models and humans.
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Giunzioni, I. "MACROPHAGE EXPRESSION OF PCSK9 INFLUENCES ATHEROSCLEROSIS DEVELOPMENT." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229332.

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Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) regulates low‐density lipoprotein (LDL) cholesterol levels by binding and degrading hepatic LDL receptor (LDLR), thus promoting atherosclerosis. Little is known of PCSK9 effect in macrophages and whether this contributes to the development of the atheroma. To test the effect of human (h) PCSK9 expression on atherosclerosis we developed transgenic mice expressing hPCSK9 on wild type (WT), LDLR‐/‐ or apoE‐/‐ background. We first demonstrated that both mPCSK9 and hPCSk9 are expressed at the mRNA level and secreted in the culture medium by MPM. As in hepatocytes, hPCSK9 reduced LDLR levels in the murine macrophage cell line J774A.1 and in inflammatory MPM. On the contrary, hPCSK9 did not reduce LRP1 expression, another member of the LDL‐R gene family involved in the development of atherosclerosis through its effects on macrophage inflammatory responses and promotion of cell survival. To test the effects of PCSK9 in the atheroma, we fed our transgenic mice a high fat diet for 8 weeks. As expected, serum cholesterol levels were increased by 2 fold in hPCSK9tg compared to WT mice (325±64 vs. 158±44 mg/dl, respectively, p<0.05) and hPCSK9 was detected in atherosclerotic plaques of hPCSK9 tg. In contrast, there was no effect of PCSK9 expression in apoE‐/‐ mice on serum cholesterol levels compared with apoE‐/‐ controls (1066±161 vs. 964±188 mg/dl, respectively, NS). Surprisingly, hPCSK9 expressing apoE‐/‐ mice showed increased proximal aorta lesion area. Lesion composition analysis revealed that lesions of PCSK9/apoE‐/‐ mice have a higher content of Ly6Chigh positive cells (6.7±0.2%) compared to apoE‐/‐ controls (5.7±0.4%). Moreover, analysis of spleen lysates revealed an increase in the percentage of Ly6Chigh positive cells in hPCSK9tg compared to control apoE‐/‐, suggesting a direct effect of PCSK9 in macrophage inflammation and plaque development. On the contrary, despite an increase in both cholesterol levels and lesion size in hPCSK9 tg/LDLR‐/‐ compared to LDLR‐/‐, no differences in Ly6Chigh positive cells were found between the two groups. To study the effect of macrophage PCSK9 in the atheroma, bone marrow cells from PCSK9/apoE‐/‐ or apoE‐/‐ mice were transplanted into apoE‐/‐ recipients. hPCSK9 was detected in serum and lesions from PCSK9/apoE‐/‐ mice but there was no effect of PCSK9 expression on serum cholesterol levels compared with apoE‐/‐ controls. Interestingly, lesion composition analysis showed significantly higher levels of Ly6Chigh positive cells in recipients of hPCSK9/apoE‐/‐ bone marrow cells compared to controls (7.4±1.5% vs. 5.6±1.1%, respectively, p<0.05). To test whether the effects of hPCSK9 on inflammation were dependent on binding and degradation of LDLR in macrophages, we transplanted bone marrow cells from PCSK9/LDLR‐/‐ or LDLR‐/‐ mice into LDLR‐/‐ recipients. We observed that, despite a large amount of PCSK9 accumulated in the serum of transgenic mice, nearly undetectable levels were found in the plaque. No differences were found between the two groups in terms of cholesterol levels, lesion size and Ly6Chigh positive cells between the two groups. Our results show for first time that human PCSK9 expression in macrophages directly influences atherosclerotic plaque composition in the absence of changes in serum cholesterol levels, suggesting a direct effect of PCSK9 in macrophage inflammation and plaque development. The effect on inflammation is dependent on LDLR since no effects in lesion composition were found in its absence.
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Stefan, Elias. "Familjär hyperkolesterolemi (FH) – analys av prevalens i Stockholm och hälsoekonomiska konsekvenser av tidigdiagnostik och behandling." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434844.

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Background: Familial hypercholesterolemia (FH) is a genetic disorder estimated to affect 0,4 % of the world's population (1 in 250). Patients with FH have abnormally high LDL-cholesterol.  Aim: The aim of this study was to estimate the prevalence of FH in Stockholm County and to evaluate the health economic impact of diagnosing people with FH early in life. Methods: Two algorithms were used to estimate the number of people with high LDLcholesterol. The first method applied data on cholesterol measurements from patients in Stockholm County between 2006-2008 and a modified version of Dutch Lipid Clinic Network. The second method was based on dispensed prescriptions of ezetimibe, lomitapide, evolucumab and alirocumab during 2019. A health economic model was created to estimate the economical outcome of diagnosing and treating patients early before undergoing a cardiovascular event. Results: The prevalence of FH in Stockholm County was estimated to 0.63 %, corresponding to a total of 12 000 individuals. The accumulated costs over 20 years for FH is estimated to be more than 1,1 billion SEK for diagnosed and treated patients, and 1,7 billion SEK for undiagnosed and untreated patients. Conclusions: The prevalence of FH in Stockholm County is probably higher than previously suggested. Early diagnosis and treatment is an investment for society and necessary for the patients to prevent cardiovascular events and improve quality of life.
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Kourimate, Sanae. "Pcsk9 : régulation et implication dans le syndrome métabolique." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=4ac185ba-f999-45ff-9241-4278a9699b5c.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) est une serine protéase, jouant un rôle important dans la régulation des niveaux de cholestérol circulant. Les mutations gains de fonctions de PCSK9 sont associées à une hypercholestérolémie autosomale dominante due à une élévation des concentrations en Low Density Lipoprotein associées au cholestérol (LDLc). A l'inverse, des mutations perte de fonction de PCSK9, sont associées à une diminution de ces concentrations et à une réduction de 88% du risque d'apparition de maladies coronariennes. Dans le réticulum endoplasmique, Pro-PCSK9 subit un autoclivage indispensable à sa maturation et à sa sécrétion. PCSK9 circulante se lie au domaine EGF-A du récepteur aux LDL (LDLR) et entraîne sa dégradation lysosomale. Tout comme le LDLR, PCSK9 est positivement régulé par les statines via le Sterol Responsive element Binding Protein -2 (SREBP2). Les statines sont très utilisées en clinique pour leurs effets hypocholestérolémiants, ajouter des inhibiteurs de PCSK9 pourrait améliorer leur efficacité. Le premier objectif a été de caractériser la régulation négative de PCSK9 par le récepteur nucléaire Peroxisome Proliferator Activated Receptor alpha (PPARα) et ses agonistes synthétiques : les fibrates. Les résultats obtenus in vitro sur des lignées d’hépatocytes humains révèlent que l’activation de PPARα réprime la transcription de PCSK9 -via une répression de son promoteur- suppriment son activation par les statines, et potentialise l’effet des statines sur l’activité du LDLR. De plus, ces résultats révélèrent que la furine et PC5/6A -deux protéines convertases qui dégradent PCSK9- sont également régulées positivement par PPARα. Au-delà de PCSK9, cette étude a permis d’identifier une nouvelle famille d’enzyme régulée par les fibrates : les pro-protéines convertases. La deuxième partie de mes travaux de thèse a porté sur la mise au point d’un test flurorométrique de dosage de l’activité autocatalytique de PCSK9. La spécificité de notre approche a été de considérer non pas la protéine recombinante purifiée, qui semble dépourvue d’activité pour une raison inconnue, mais la forme endogène des hépatocytes. Après avoir validé ce test sur des hépatocytes primaires de souris PCSK9-/-, je l’ai appliqué à l’étude de divers mutants de PCSK9. Enfin, suite aux travaux du laboratoire sur la régulation de PCSK9 par l'insuline, j’ai également caractérisé l’expression de PCSK9 dans divers modèles animaux de diabète et d’insulinorésistance. PCSK9 est une cible thérapeutique sérieuse pour diminuer le LDL-c. D'après ces résultats, l’inhibition transcriptionnelle de PCSK9 par les fibrates semble être très prometteuse. Cependant, en clinique les fibrates sont préférentiellement utilisés pour leurs propriétés hypotriglycéridémiantes, puisque leurs effets sur le cholestérol restent limités. Existerait-il in vivo un mécanisme inhibiteur de cette voie? L'identifier serait une des perspectives qu'ouvre cette thèse
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the serine protease family. Gain of function mutations within PCSK9 are associated with dominant forms of familial hypercholesterolemia. Inversely, humans harbouring loss of function mutations have a significant plasma LDLc reduction and a 88% decrease of the risk of coronary heart disease. In the endoplasmic reticulum Pro-PCSK9 undergoes an autocalytique clivage that is crucial for its secretion. Then, this secreted protein binds to the EGF-A domain of the LDLR and targets it to the lysosomes rather than to the cell surface. Both PCSK9 and the LDLR are up-regulated by statins via SREBP2. Using PCSK9 inhibitors may optimize the effects of this hypocholesterolemic drug. The first aim of my thesis was to investigate in vitro the mechanisms of PCSK9 repression by the fibrates which are PPARα synthetic agonists. Activation of PPARα down-regulates PCSK9 transcription at the promoter level and increase the expression of two others Proprotein convertases: furin and PC5/6A which are known to degrade PCSK9. Fibrates counteracts PCSK9 induction by statins and amplifies the effects of this hypocholesterolemic drugs on the LDLR acitivity. The second part of my studies was based on measuring the endogenous cleavage activity of PCSK9, using a fluorogenic peptide corresponding to the cleavage site of Pro-PCSK9. After validation of the specificity of this assay on mice primary hepatocytes from PCSK9-/-, I applied it to the test of several PCSK9 variants. The final part of my studies dealt about the characterisation of PCSK9 expression in diabetic and insulin resistant animal models. PCSK9 is an attractive therapeutic target for lowering plasma LDLc levels. This study clearly showed that PCSK9 transcriptional inhibition by fibrates might be envisaged in combination with statins. However, in vivo, in humans, the fibrates are rather known for their hypotriglyceridemic properties. The limited effect of fibrates on lowering LDLc might be explained by a counteracting pathway. Identifying this pathway is one of the promising perspectives of this thesis
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CANCLINI, LAURA. "PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 PREFERENTIALLY ASSOCIATES WITH A SPECIFIC LDL SUBFRACTION: A DETAILED CHARACTERIZATION AND STUDY OF THE EFFECTS OF ANTI-PCSK9 MABS TREATMENT." Doctoral thesis, Università degli Studi di Milano, 2022. https://hdl.handle.net/2434/947250.

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BACKGROUND AND AIM: Proprotein Convertase Subtilysin/Kexin Type 9 is a key regulator of LDL-C levels. Nevertheless, its physiological modulation is not fully understood. It is unclear whether PCSK9 has biological effects other than degrading the LDLR; consensus is lacking also on how PCSK9 is transported in the bloodstream, and whether this influences PCSK9 function. There are several conflicting data about PCSK9’s possible association with different lipoprotein subtypes. The biological function of the lipoprotein-bound PCSK9, also, is still a matter of debate. Due to its role in modulating plasma cholesterol levels, several approaches have been developed to modulate PCSK9 activity. Anti-PCSK9 mAbs represent the most advanced clinical available strategy for PCSK9 pharmacological inhibition, followed by the siRNA approach which seems promising. In this context, our aims were: 1) to establish a valid experimental procedure for the study of the possible association between PCSK9 and plasma lipoproteins. This would help us reach a clear idea about PCSK9’s lipoprotein compartmentation. 2) To characterize the lipoprotein fraction that binds PCSK9; 3) to address whether anti-PCSK9 mAbs therapy interferes with the PCSK9-LPs association, with resulting biological consequences. The capacity of PCSK9 to bind different lipoproteins raises the possibility that changes in the lipoprotein compartmentalization could regulate PCSK9 activity, and mAbs possible effects on such interaction may have biological consequences thus affecting their own pharmacological action. The study of such regulatory mechanisms could represent a potential avenue for developing new cholesterol-lowering drugs. METHODS: To reach our first aim, we compared several well-established methods in the lipoprotein isolation technique to clarify whether PCSK9 associates differently with circulating lipoproteins. The lipoprotein fractions collected were quantified for their cholesterol, triglycerides, PCSK9, apoB, apo AI and Lp(a) content using clinical grade reactives or ELISA. They were further characterized through immunoblotting, agarose gel electrophoresis, transmission electron microscopy (TEM), lipidomic and mass spectrometry. Following this, we analyzed PCSK9’s lipoprotein distribution among OptiPrep UC-isolated lipoproteins, obtained from anti-PCSK9 mAbs treated subjects before therapy (T0), and 1 (T1), 3 (T3) and 6 (T6) months after the beginning of treatment. The collected lipoprotein fractions were further characterized as described above. RESULTS AND CONCLUSION: Based on our results, the PCSK9-LDL association exists and is sensitive to high salt concentrations. OptiPrep UC and FPLC are both suitable methods for the study of this association. We believe that PCSK9 circulates mostly as a free type of protein, and partially (approx. 10-20% of total recovered PCSK9) associated through its active form with a light LDL subfraction resembling an IDL. We believe that this association originates in the circulation, as we did not find PCSK9 in the VLDL-containing fractions. PCSK9 did not associate with Lp(a) or HDL. Anti-PCSK9 mAbs administration induced a large decrease in LDL-C levels, - from 140,3±64,8 mg/dL to 51,5±35,6 mg/dL before and after treatment, respectively - parallel with a drastic increase in PCSK9 plasma levels - from 409,4±123,3 ng/mL to 3802,3±1001,0 ng/mL (n=22); despite this, they did not affect the PCSK9-LDL association but instead induce a more than 10-fold increase in the absolute quantity of LDL-bound PCSK9. Interestingly, the amount of PCSK9 recovered in the LDL fractions after therapy was about 242,3±164,8 ng/mL, like that of plasma of untreated subjects; this suggested that the LDL-bound PCSK9 may be inactive. Preliminary data obtained from Inclisiran-treated subjects suggest that the PCSK9- LDL association is maintained also when reducing both LDL and PCSK9 levels, therefore reinforcing the idea that the PCSK9-LDL association might be biologically meaningful.
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Dewpura, Thilina. "Importance of phosphorylation in PCSK9 processing, stability and function." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28604.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted glycoprotein regulating the degradation of low density lipoprotein receptor. Single nucleotide polymorphisms in PCSK9 associate with both hyper- and hypo-cholesterolemia; studies show significant reduction in risk of coronary heart disease for 'loss of function' PCSK9 carriers. We used a combination of mass spectrometry and radiolabeling to report that PCSK9 is phosphorylated at two sites, Ser47 in its propeptide, and Ser688 in its C-terminus. Site directed mutagenesis (SDM) demonstrated that a Golgi casein kinase-like kinase was responsible for PCSK9 phosphorylation based on the consensus site, SXE/S(p). PCSK9 phosphorylation is cell-type specific; phosphorylation status did not affect PCSK9 processing or secretion. Phosphorylated PCSK9 propeptide is protected against proteolysis. Immunoblotting demonstrated that PCSK9 mutants engineered by SDM to prevent phosphorylation at either site (substitution to Ala) or in combination resulted in significantly increased LDLR levels in HuH7 cells by up to -25%. PCSK9 mutants engineered by SDM to mimick phosphorylation (substitution to Asp/Glu) at the N-terminus, but not at the C-terminus or in combination, promoted LDLR degradation significantly more than wild-type. Far western analysis demonstrated that preventing PCSK9 phosphorylation promoted its interaction with the endogenous inhibitor Annexin A2.
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Roubtsova, Anna. "Partial hepatectomy and liver regeneration in PCSK9 knockout mice." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112356.

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The proprotein convertase subtilisin/kexin type 9, PCSK9, belongs to the proprotein convertase (PC) family. Human mutations in the gene encoding PCSK9 lead to either familial hyper- or hypocholesterolemia, resulting from a gain or loss of function, respectively. Mice lacking PCSK9 are viable and show a 42% decrease in plasma cholesterol levels. The enzyme triggers the degradation of the low density lipoprotein receptor (LDLR) through a partially unknown mechanism.
PCSK9 is very abundant in the liver and intestine during development and adulthood. Hepatocytes have a capacity to reproduce themselves and, upon injury, can repopulate the liver. For a better understanding of the role of PCSK9 in the liver, partial hepatectomy was performed on Pcsk9 +/+, Pcsk9+/- and Pcsk9-/- mice. The absence of PCSK9 resulted in defective liver regeneration, while wild type (WT) and heterozygous mice had no phenotype. Regeneration defects could be prevented by a high cholesterol diet. PCSK9 deficiency, by contributing to maintaining low circulating cholesterol levels may thus hamper liver regeneration. This knowledge is critical for the analysis of future PCSK9 inhibitors expected to be developed in the near future.
Key words. Proprotein convertase subtilisin/kexin 9 (PCSK9), a familial hyper- or hypocholesterolemia, low density lipoprotein receptor, knockout mouse model, partial hepatectomy.
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Torrinha, José Maria de Queiroz e. Lencastre Fleming. "Inibidores PCSK9: nova estratégia para o tratamento da hipercolesterolemia." Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5293.

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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
As doenças cardiovasculares são uma das principais causas de morbilidade e mortalidade a nível mundial. Neste enquadramento, um dos principais fatores de risco associado às doenças cardiovasculares é a hipercolesterolemia. As opções farmacológicas existentes para o tratamento e prevenção desta dislipidemia centram-se, sobretudo, no uso de fármacos como as estatinas, a ezetimiba, os fibratos, o ácido nicotínico e as resinas sequestradoras de ácidos biliares. Porém, esta abordagem farmacológica no combate da hipercolesterolemia caracteriza-se pelo prolongado período terapêutico decorrendo daí possíveis efeitos laterais a longo prazo, pela intolerância a grupos terapêuticos observada em alguns doentes (como acontece com as estatinas) ou, ainda, pela eficácia limitada de alguns grupos terapêuticos (como é o caso, dos fibratos), o que suscita preocupação. Os avanços científicos no conhecimento dos processos que envolvem a hipocolesterolemia e a incessante procura de fármacos mais seguros e eficazes impulsionou o desenvolvimento dos inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9), afirmando-se como uma nova e promissora estratégia terapêutica. Os níveis plasmáticos elevados de colesterol proveniente das lipoproteínas de baixa densidade (C-LDL) são um fator de risco, no desenvolvimento de aterosclerose e de doença vascular isquémica. O recetor LDL (R-LDL) é essencial no metabolismo do colesterol, uma vez que ao se ligar ao C-LDL é capaz de eliminá-lo da circulação. É aqui, que reside o principal foco de interesse desta nova estratégia terapêutica, uma vez que a PCSK9 promove a degradação do recetor R-LDL, conduzindo a uma redução da depuração de LDL, aumentando os níveis de colesterol LDL. Desta forma, a inibição da atividade da PCSK9, veio revelar-se como uma nova abordagem potencialmente interessante para o desenvolvimento de novos fármacos destinados à redução do C-LDL. Os anticorpos monoclonais humanos contra PCSK9 estão em desenvolvimento clínico e são, neste momento, a aposta mais promissora de inibição da PCSK9. Até ao momento, os resultados dos ensaios clínicos demonstraram a eficácia destas moléculas com redução do C-LDL na ordem dos 60%. Adicionalmente, os seus efeitos na redução do C-LDL são aditivos aos das estatinas e até à data, não mostraram qualquer efeito tóxico a nível muscular, como acontece com estas últimas, sendo fármacos bem tolerados e aparentemente seguros.
Cardiovascular diseases are a major cause of morbidity and mortality worldwide. In this context, one of the main risk factor associated with cardiovascular disease is hypercholesterolemia. The treatment and prevention of this dyslipidemia is mainly focused on the use of drugs such as statins, ezetimibe, fibrates, nicotinic acid and bile acid sequestrants. However, the pharmacological approach in hypercholesterolemia treatment is characterized by prolonged therapeutic period elapsing possible long-term side effects, by the intolerance to treatment in some patients (as is the case of statins), or by the limited efficacy of various drugs/pharmaceuticals (as for example of fibrates), which raise concerns. Scientific advances in the understanding of hypercholesterolemia and the constant need for safer and more effective drugs prompted the development of the convertase pro-protein subtilisin inhibitor/kexin type 9 (PCSK9), as a promising new therapeutic strategy. Elevated plasma LDL cholesterol (LDL-C) levels are a risk factor for atherosclerosis and ischemic vascular disease. The LDL receptor (LDL-R) has an essential role in the cholesterol metabolism, since it binds to LDL-C removing it from circulation. Here, lies the main focus of interest of this novel therapeutic strategy, since PCSK9 promotes LDL-R the degradation, leading to a reduction of LDL clearance, increasing levels of LDL cholesterol. Therefore, inhibition of PCSK9 activity is a potentially interesting new approach for the development of new drugs to reduce LDL-C. Human monoclonal antibodies against PCSK9 are in clinical development and are presently the most promising strategy for the inhibition of PCSK9. At the moment, results of clinical trials show the efficacy of these molecules with reductions efficiencies of LDL-C in the order of 60%. Furthermore, this LDL-C reduction are additive to those of statins and until now have not shown any toxic effect in muscle, as observed with statins, and have a good record for safety and tolerability.
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Books on the topic "PCSK7"

1

Xu, Weiming. New Cardiovascular Research: PCSK9 As a New Therapeutic Target for Cardiovascular Disease. Independently Published, 2021.

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Muller, Jurgen. Regeln Mit Simatic: Praxisbuch Fr Regelungen Mit Simatic S7 Und Simatic PCs7. Not Avail, 2003.

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Controlling with SIMATIC: Practice Book for SIMATIC S7 and SIMATIC PCS7 Control Systems. Wiley-VCH, 2005.

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Müller, Jürgen, Bernd-Markus Pfeiffer, and Roland Wieser. Regeln Mit SIMATIC: Praxisbuch Für Regelungen Mit SIMATIC und SIMATIC S7 PCS7 Für Die Prozessautomatisierung. Publicis MCD Werbeagentur GmbH, 2020.

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Regeln mit SIMATIC: Praxisbuch für Regelungen mit SIMATIC S7 und SIMATIC PCS7 für die Prozessautomatisierung. Wiley & Sons, Limited, John, 2011.

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Müller, Jürgen, Bernd-Markus Pfeiffer, and Roland Wieser. Regeln Mit SIMATIC: Praxisbuch Für Regelungen Mit SIMATIC und SIMATIC S7 PCS7 Für Die Prozessautomatisierung. Publicis MCD Werbeagentur GmbH, 2012.

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Atta-ur-Rahman and M. Iqbal Choudhary, eds. Frontiers in Cardiovascular Drug Discovery: Volume 4. BENTHAM SCIENCE PUBLISHERS, 2019. http://dx.doi.org/10.2174/97816810839951180401.

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Frontiers in Cardiovascular Drug Discovery is an eBook series devoted to publishing the latest advances in cardiovascular drug design and discovery. Each volume brings reviews on the biochemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships of molecules used in cardiovascular therapy. The eBook series should prove to be of great interest to all medicinal chemists and pharmaceutical scientists involved in preclinical and clinical research in cardiology. The fourth volume of the series covers the following topics: -Aspirin administration -Adenosine receptor targeting for cardiovascular therapy -Drug treatment of patients with coronary stenting -Immunosuppressive drugs in heart transplantation -PCSK9 inhibition for lowering LDL-C levels.
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Book chapters on the topic "PCSK7"

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Wright, R. Scott. "PCSK9 Inhibiting siRNA." In Stroke Revisited: Dyslipidemia in Stroke, 135–43. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-3923-4_12.

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Ahmed, Zain, Prerak Juthani, Megan Lee, and Nihar R. Desai. "PCSK9 Inhibiting Monoclonal Antibodies." In Stroke Revisited: Dyslipidemia in Stroke, 125–33. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-3923-4_11.

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Desnick, Robert J., Orlando Guntinas-Lichius, George W. Padberg, Gustav Schonfeld, Xiaobo Lin, Maurizio Averna, Pin Yue, et al. "FHBL due to Defective PCSK9." In Encyclopedia of Molecular Mechanisms of Disease, 653. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_8889.

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Choquet, Hélène, Pieter Stijnen, and John W. M. Creemers. "Genetic and Functional Characterization of PCSK1." In Methods in Molecular Biology, 247–53. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-204-5_13.

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Wang, Zuo, Zhi-Han Tang, Yun-Chen Lv, Lu-Shan Liu, and Zhi-Sheng Jiang. "Bioinformatic Analysis of PCSK9 Related Caspase3 Activation." In Recent Advances in Computer Science and Information Engineering, 527–33. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-25778-0_73.

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Ooi, Teik Chye, and Hussein Abujrad. "PCSK9 as a Biomarker of Cardiovascular Disease." In Biomarkers in Cardiovascular Disease, 125–51. Dordrecht: Springer Netherlands, 2016. http://dx.doi.org/10.1007/978-94-007-7678-4_20.

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Ooi, Teik Chye, and Hussein Abujrad. "PCSK9 as a Biomarker of Cardiovascular Disease." In Biomarkers in Cardiovascular Disease, 1–27. Dordrecht: Springer Netherlands, 2015. http://dx.doi.org/10.1007/978-94-007-7741-5_20-1.

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Farnier, Michel. "Statins and PCSK9 Inhibitors: Defining the Correct Patients." In Combination Therapy In Dyslipidemia, 99–117. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-20433-8_9.

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Innocenti, Francesca, Valentina Di Maria, Alice Poggi, and Riccardo Pini. "Biomarkers of Sepsis and a Focus on PCSK9." In Biomarkers in Trauma, Injury and Critical Care, 1–28. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-87302-8_40-1.

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Pandey, Pratik, Cuimei Zhao, and Ban Liu. "PCSK9 Inhibition and Atherosclerosis: Current Therapeutic Option and Prospection." In Methods in Molecular Biology, 133–43. New York, NY: Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0904-0_12.

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Conference papers on the topic "PCSK7"

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Stickel, F., S. Buch, E. Ryan, M. Way, H. Zoller, W. Griffith, KH Weiss, et al. "TM6SF2 rs58542926 und PCSK7 rs236918 sind genetische Risikoloci einer Leberzirrhose bei hereditärer Hämochromatose." In Viszeralmedizin 2017. Georg Thieme Verlag KG, 2017. http://dx.doi.org/10.1055/s-0037-1604986.

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Buch, S., F. Stickel, H. Zoller, E. Ryan, AD Sharma, E. Aigner, WJH Griffiths, et al. "Variants in TM6SF2, PNPLA3 and PCSK7 are risk factors for the development of cirrhosis in people with genetic haemochromatosis." In 35. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0038-1677064.

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Martin Plagaro, Cesar, Kepa B. Uribe, Asier Benito Vicente, Rocio Alonso Estraba, Unai Galicia Garcia, Shifa Jebari Benslaiman, and Asier Larrea Sebal. "Hiperkolesterolemia Familiarra: PCSK9 aldaeren karakterizazioa tratamendu pertsonalizaturako." In III. Ikergazte. Nazioarteko ikerketa euskaraz. Bilbao: UEU arg, 2019. http://dx.doi.org/10.26876/ikergazte.iii.04.10.

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Niemann, B., L. Li, F. Knapp, R. Schulz, and S. Rohrbach. "Modifying Epicardial PCSK9 Expression to Protect Cardiac Function?" In 48th Annual Meeting German Society for Thoracic, Cardiac, and Vascular Surgery. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1678923.

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Sha, Xiangtong, and Yueqiang Wang. "PCSK1 Variants and Obesity: Relationship in Different Population." In 2021 International Conference on Public Art and Human Development ( ICPAHD 2021). Paris, France: Atlantis Press, 2022. http://dx.doi.org/10.2991/assehr.k.220110.187.

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Lecis, M., E. Viglione, S. Strobino, and G. Ceravolo. "5PSQ-017 PCSK-9 inhibitors: real world effectiveness." In 25th EAHP Congress, 25th–27th March 2020, Gothenburg, Sweden. British Medical Journal Publishing Group, 2020. http://dx.doi.org/10.1136/ejhpharm-2020-eahpconf.334.

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Martin, V. Merino, MP Ortega-Garcia, P. Blasco-Segura, J. Sanfeliu Garcia, A. Lopez Carrasco, R. del Rio San Cristobal, and I. Toledo Guasp. "4CPS-035 Effectiveness and safety of monoclonal antibody pcsk9 inhibitors." In Abstract Book, 23rd EAHP Congress, 21st–23rd March 2018, Gothenburg, Sweden. British Medical Journal Publishing Group, 2018. http://dx.doi.org/10.1136/ejhpharm-2018-eahpconf.126.

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Ly, Kévin, Anna Kwiatkowska, Sophie Routhier, Roxane Desjardins, Monika Lewandowska, Adam Prahl, Josée Hamelin, Nabil G. Seidah, Yves Dory, and Robert Day. "Development of Peptide Inhibitors Disrupting PCSK9-LDLR Protein-Protein Interactions." In The Twenty-Third American and the Sixth International Peptide Symposium. Prompt Scientific Publishing, 2013. http://dx.doi.org/10.17952/23aps.2013.110.

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Sáez Rodríguez, MI, JJ Arenas Villafranca, B. Montero Salgado, PA Chinchurreta Capote, and B. Tortajada Goitia. "4CPS-119 Real-world experience with PCSK9 inhibitors protocol for hypercholesterolaemia." In 26th EAHP Congress, Hospital pharmacists – changing roles in a changing world, 23–25 March 2022. British Medical Journal Publishing Group, 2022. http://dx.doi.org/10.1136/ejhpharm-2022-eahp.146.

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Asadipooya, Hanieh, and Ali Akbar Safavi. "Enhancement of model predictive control implementation on a DCS PCS7." In 2016 24th Iranian Conference on Electrical Engineering (ICEE). IEEE, 2016. http://dx.doi.org/10.1109/iraniancee.2016.7585717.

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Reports on the topic "PCSK7"

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Yu, Yani, Lei Chen, Honghong Zhang, Zihao Fu, Qi Liu, Haijing Zhao, Yuqi Liu, and Yundai Chen. Racial differences in the safety and efficacy of PCSK9 inhibitors in the treatment of hyperlipidemia：A Systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, November 2021. http://dx.doi.org/10.37766/inplasy2021.11.0047.

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Niu, Xiaowei, and Shuwen Hu. Efficacy and safety of PCSK9 inhibitors and statin lipid-lowering therapy in coronary atherosclerosis: A meta-analysis of randomized trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, December 2022. http://dx.doi.org/10.37766/inplasy2022.12.0019.

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You might also be interested in the extended bibliographies on the topic 'PCSK7' for particular source types:
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