{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T06:57:26Z","timestamp":1791615446419,"version":"4.3.4"},"reference-count":171,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,30]],"date-time":"2021-05-30T00:00:00Z","timestamp":1622332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin\/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.<\/jats:p>","DOI":"10.3390\/ijms22115880","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:22:15Z","timestamp":1622420535000},"page":"5880","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":158,"title":["PCSK9 Biology and Its Role in Atherothrombosis"],"prefix":"10.3390","volume":"22","author":[{"given":"Cristina","family":"Barale","sequence":"first","affiliation":[{"name":"Department of Clinical and Biological Sciences, Turin University, I-10043 Orbassano, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Melchionda","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, Turin University, I-10043 Orbassano, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8407-2903","authenticated-orcid":false,"given":"Alessandro","family":"Morotti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, Turin University, I-10043 Orbassano, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2921-1763","authenticated-orcid":false,"given":"Isabella","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, Turin University, I-10043 Orbassano, TO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.gheart.2018.09.511","article-title":"Global Atlas of Cardiovascular Disease 2000-2016: The Path to Prevention and Control","volume":"13","author":"Thomas","year":"2018","journal-title":"Glob. Heart"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1001\/jama.2016.13985","article-title":"Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-Analysis","volume":"316","author":"Silverman","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cholesterol Treatment Trialists\u2019 (CTT) Collaborators, Mihaylova, B., Emberson, J., Blackwell, L., Keech, A., Simes, J., Barnes, E.H., Voysey, M., Gray, A., and Collins, R. (2012). The Effects of Lowering LDL Cholesterol with Statin Therapy in People at Low Risk of Vascular Disease: Meta-Analysis of Individual Data from 27 Randomised Trials. Lancet, 380, 581\u2013590.","DOI":"10.1016\/S0140-6736(12)60367-5"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1111\/j.1365-2796.2009.02167.x","article-title":"The Unique Role of Proprotein Convertase Subtilisin\/Kexin 9 in Cholesterol Homeostasis","volume":"266","author":"Mousavi","year":"2009","journal-title":"J. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1093\/eurheartj\/ehx144","article-title":"Low-Density Lipoproteins Cause Atherosclerotic Cardiovascular Disease. 1. Evidence from Genetic, Epidemiologic, and Clinical Studies. A Consensus Statement from the European Atherosclerosis Society Consensus Panel","volume":"38","author":"Ference","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cholesterol Treatment Trialists\u2019 (CTT) Collaboration, Baigent, C., Blackwell, L., Emberson, J., Holland, L.E., Reith, C., Bhala, N., Peto, R., Barnes, E.H., and Keech, A. (2010). Efficacy and Safety of More Intensive Lowering of LDL Cholesterol: A Meta-Analysis of Data from 170,000 Participants in 26 Randomised Trials. Lancet, 376, 1670\u20131681.","DOI":"10.1016\/S0140-6736(10)61350-5"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1056\/NEJMoa1816454","article-title":"20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia","volume":"381","author":"Luirink","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.phrs.2019.03.021","article-title":"Cardiovascular Events with PCSK9 Inhibitors: An Updated Meta-Analysis of Randomised Controlled Trials","volume":"143","author":"Casula","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_9","unstructured":"Macchi, C., Ferri, N., Sirtori, C.R., Corsini, A., Banach, M., and Ruscica, M. (2021). PCSK9: A View beyond the Canonical Cholesterol Lowering Impact. Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/ng1161","article-title":"Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia","volume":"34","author":"Abifadel","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.atherosclerosis.2009.02.006","article-title":"Commentary PCSK9 Variants: A New Database","volume":"203","author":"Leigh","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/ng1509","article-title":"Low LDL Cholesterol in Individuals of African Descent Resulting from Frequent Nonsense Mutations in PCSK9","volume":"37","author":"Cohen","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1056\/NEJMoa054013","article-title":"Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease","volume":"354","author":"Cohen","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1086\/507488","article-title":"Molecular Characterization of Loss-of-Function Mutations in PCSK9 and Identification of a Compound Heterozygote","volume":"79","author":"Zhao","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.atherosclerosis.2006.08.039","article-title":"The C679X Mutation in PCSK9 Is Present and Lowers Blood Cholesterol in a Southern African Population","volume":"193","author":"Hooper","year":"2007","journal-title":"Atherosclerosis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/pro.5560060301","article-title":"Subtilases: The Superfamily of Subtilisin-like Serine Proteases","volume":"6","author":"Siezen","year":"1997","journal-title":"Protein Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D227","DOI":"10.1093\/nar\/gkp971","article-title":"MEROPS: The Peptidase Database","volume":"38","author":"Rawlings","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1126\/science.1205677","article-title":"A Key Enzyme in the Biogenesis of Lysosomes Is a Protease That Regulates Cholesterol Metabolism","volume":"333","author":"Marschner","year":"2011","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Turpeinen, H., Kukkurainen, S., Pulkkinen, K., Kauppila, T., Ojala, K., Hyt\u00f6nen, V.P., and Pesu, M. (2011). Identification of Proprotein Convertase Substrates Using Genome-Wide Expression Correlation Analysis. BMC Genom., 12.","DOI":"10.1186\/1471-2164-12-618"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1515\/BMC.2011.034","article-title":"On the Cutting Edge of Proprotein Convertase Pharmacology: From Molecular Concepts to Clinical Applications","volume":"2","author":"Couture","year":"2011","journal-title":"Biomol. Concepts"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20799","DOI":"10.1074\/jbc.C700095200","article-title":"Catalytic Activity Is Not Required for Secreted PCSK9 to Reduce Low Density Lipoprotein Receptors in HepG2 Cells","volume":"282","author":"McNutt","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1073\/pnas.0402133101","article-title":"Adenoviral-Mediated Expression of Pcsk9 in Mice Results in a Low-Density Lipoprotein Receptor Knockout Phenotype","volume":"101","author":"Maxwell","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"48865","DOI":"10.1074\/jbc.M409699200","article-title":"NARC-1\/PCSK9 and Its Natural Mutants: Zymogen Cleavage and Effects on the Low Density Lipoprotein (LDL) Receptor and LDL Cholesterol","volume":"279","author":"Benjannet","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00109-007-0172-7","article-title":"The Proprotein Convertases Are Potential Targets in the Treatment of Dyslipidemia","volume":"85","author":"Seidah","year":"2007","journal-title":"J. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrd3699","article-title":"The Biology and Therapeutic Targeting of the Proprotein Convertases","volume":"11","author":"Seidah","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.str.2007.04.004","article-title":"The Crystal Structure of PCSK9: A Regulator of Plasma LDL-Cholesterol","volume":"15","author":"Piper","year":"2007","journal-title":"Structure"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1002\/cmdc.202000431","article-title":"Exploring Proprotein Convertase Subtilisin\/Kexin 9 (PCSK9) Autoproteolysis Process by Molecular Simulations: Hints for Drug Design","volume":"15","author":"Sgrignani","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1073\/pnas.0712064105","article-title":"Molecular Basis for LDL Receptor Recognition by PCSK9","volume":"105","author":"Kwon","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1016\/j.celrep.2015.11.006","article-title":"GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation","volume":"13","author":"Poirier","year":"2015","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28856","DOI":"10.1074\/jbc.M109.037085","article-title":"Dissection of the Endogenous Cellular Pathways of PCSK9-Induced Low Density Lipoprotein Receptor Degradation: Evidence for an Intracellular Route","volume":"284","author":"Poirier","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1161\/CIRCULATIONAHA.113.001592","article-title":"Serum Proprotein Convertase Subtilisin\/Kexin Type 9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal Regulation","volume":"127","author":"Tavori","year":"2013","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8279","DOI":"10.1074\/jbc.M112.421370","article-title":"Low Density Lipoprotein Binds to Proprotein Convertase Subtilisin\/Kexin Type-9 (PCSK9) in Human Plasma and Inhibits PCSK9-Mediated Low Density Lipoprotein Receptor Degradation","volume":"288","author":"Kosenko","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30561","DOI":"10.1074\/jbc.M606495200","article-title":"The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and\/or PC5\/6A: Functional Consequences of Natural Mutations and Post-Translational Modifications","volume":"281","author":"Benjannet","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"43482","DOI":"10.1074\/jbc.M112.380618","article-title":"Furin-Cleaved Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Is Active and Modulates Low Density Lipoprotein Receptor and Serum Cholesterol Levels","volume":"287","author":"Lipari","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.tibs.2006.12.008","article-title":"Molecular Biology of PCSK9: Its Role in LDL Metabolism","volume":"32","author":"Horton","year":"2007","journal-title":"Trends Biochem. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S172","DOI":"10.1194\/jlr.R800091-JLR200","article-title":"PCSK9: A Convertase That Coordinates LDL Catabolism","volume":"50","author":"Horton","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.5551\/jat.27615","article-title":"PCSK9: A Key Factor Modulating Atherosclerosis","volume":"22","author":"Li","year":"2015","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1161\/CIRCRESAHA.114.301621","article-title":"PCSK9: A Key Modulator of Cardiovascular Health","volume":"114","author":"Seidah","year":"2014","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1111\/j.1742-4658.2011.08219.x","article-title":"Affinity and Kinetics of Proprotein Convertase Subtilisin\/Kexin Type 9 Binding to Low-Density Lipoprotein Receptors on HepG2 Cells","volume":"278","author":"Mousavi","year":"2011","journal-title":"FEBS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/eurheartj\/ehz566","article-title":"Cyclase-Associated Protein 1 Is a Binding Partner of Proprotein Convertase Subtilisin\/Kexin Type-9 and Is Required for the Degradation of Low-Density Lipoprotein Receptors by Proprotein Convertase Subtilisin\/Kexin Type-9","volume":"41","author":"Jang","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1074\/jbc.M708098200","article-title":"The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2","volume":"283","author":"Poirier","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e64145","DOI":"10.1371\/journal.pone.0064145","article-title":"Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Can Mediate Degradation of the Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1)","volume":"8","author":"Canuel","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"50630","DOI":"10.1074\/jbc.M410077200","article-title":"Post-Transcriptional Regulation of Low Density Lipoprotein Receptor Protein by Proprotein Convertase Subtilisin\/Kexin Type 9a in Mouse Liver","volume":"279","author":"Park","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/cvr\/cvw053","article-title":"Human PCSK9 Promotes Hepatic Lipogenesis and Atherosclerosis Development via ApoE- and LDLR-Mediated Mechanisms","volume":"110","author":"Tavori","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1161\/ATVBAHA.112.250043","article-title":"Proprotein Convertase Subtilisin\/Kexin Type 9 Interacts with Apolipoprotein B and Prevents Its Intracellular Degradation, Irrespective of the Low-Density Lipoprotein Receptor","volume":"32","author":"Sun","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.atherosclerosis.2013.01.023","article-title":"PCSK9 Plays a Significant Role in Cholesterol Homeostasis and Lipid Transport in Intestinal Epithelial Cells","volume":"227","author":"Levy","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1161\/ATVBAHA.110.220988","article-title":"Circulating Proprotein Convertase Subtilisin\/Kexin 9 (PCSK9) Regulates VLDLR Protein and Triglyceride Accumulation in Visceral Adipose Tissue","volume":"31","author":"Roubtsova","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1161\/CIRCULATIONAHA.113.006720","article-title":"Proprotein Convertase Subtilisin Kexin Type 9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein B Lipoproteins through Both Low-Density Lipoprotein Receptor-Dependent and -Independent Mechanisms","volume":"130","author":"Rashid","year":"2014","journal-title":"Circulation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.bbrc.2008.07.106","article-title":"PCSK9 Binds to Multiple Receptors and Can Be Functionally Inhibited by an EGF-A Peptide","volume":"375","author":"Shan","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.jacl.2011.04.003","article-title":"Familial Hypercholesterolemia: Screening, Diagnosis and Management of Pediatric and Adult Patients: Clinical Guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia","volume":"5","author":"Goldberg","year":"2011","journal-title":"J. Clin. Lipidol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.atherosclerosis.2005.02.016","article-title":"Genetic Screening Protocol for Familial Hypercholesterolemia Which Includes Splicing Defects Gives an Improved Mutation Detection Rate","volume":"182","author":"Graham","year":"2005","journal-title":"Atherosclerosis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.cca.2014.01.043","article-title":"PCSK9 Gene Mutations and Low-Density Lipoprotein Cholesterol","volume":"431","author":"Wu","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.atherosclerosis.2011.04.018","article-title":"Clinical Aspects of PCSK9","volume":"216","author":"Cariou","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1073\/pnas.0409736102","article-title":"Overexpression of PCSK9 Accelerates the Degradation of the LDLR in a Post-Endoplasmic Reticulum Compartment","volume":"102","author":"Maxwell","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5374","DOI":"10.1073\/pnas.0501652102","article-title":"Decreased Plasma Cholesterol and Hypersensitivity to Statins in Mice Lacking Pcsk9","volume":"102","author":"Rashid","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.0009-9163.2004.0238.x","article-title":"Mutations in the PCSK9 Gene in Norwegian Subjects with Autosomal Dominant Hypercholesterolemia","volume":"65","author":"Leren","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s00439-003-1071-9","article-title":"A Mutation in PCSK9 Causing Autosomal-Dominant Hypercholesterolemia in a Utah Pedigree","volume":"114","author":"Timms","year":"2004","journal-title":"Hum. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1161\/ATVBAHA.114.304406","article-title":"PCSK9 R46L, Lower LDL, and Cardiovascular Disease Risk in Familial Hypercholesterolemia: A Cross-Sectional Cohort Study","volume":"34","author":"Saavedra","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.numecd.2011.06.002","article-title":"Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9): From Structure-Function Relation to Therapeutic Inhibition","volume":"21","author":"Tibolla","year":"2011","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.atherosclerosis.2009.02.012","article-title":"Cellular and Secreted Pro-Protein Convertase Subtilisin\/Kexin Type 9 Catalytic Activity in Hepatocytes","volume":"206","author":"Kourimate","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Poirier, S., Hamouda, H.A., Villeneuve, L., Demers, A., and Mayer, G. (2016). Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157230"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.atherosclerosis.2008.10.007","article-title":"Mutation S462P in the PCSK9 Gene Reduces Secretion of Mutant PCSK9 without Affecting the Autocatalytic Cleavage","volume":"203","author":"Cameron","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1253\/circj.CJ-15-0999","article-title":"Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Gain-of-Function Mutations","volume":"80","author":"Tada","year":"2016","journal-title":"Circ. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1161\/CIRCRESAHA.114.302721","article-title":"Mechanisms of Plaque Formation and Rupture","volume":"114","author":"Bentzon","year":"2014","journal-title":"Circ. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1073\/pnas.0335507100","article-title":"The Secretory Proprotein Convertase Neural Apoptosis-Regulated Convertase 1 (NARC-1): Liver Regeneration and Neuronal Differentiation","volume":"100","author":"Seidah","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.atherosclerosis.2011.11.026","article-title":"Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Secreted by Cultured Smooth Muscle Cells Reduces Macrophages LDLR Levels","volume":"220","author":"Ferri","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1093\/cvr\/cvv178","article-title":"Cross-Talk between LOX-1 and PCSK9 in Vascular Tissues","volume":"107","author":"Ding","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1089\/ars.2016.6631","article-title":"Cross-Talk Between PCSK9 and Damaged MtDNA in Vascular Smooth Muscle Cells: Role in Apoptosis","volume":"25","author":"Ding","year":"2016","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1089\/ars.2014.6054","article-title":"Hemodynamic Shear Stress via ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and along the Mouse Aorta","volume":"22","author":"Ding","year":"2015","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1161\/01.CIR.0000136032.40666.3D","article-title":"Aggregated Low-Density Lipoprotein Uptake Induces Membrane Tissue Factor Procoagulant Activity and Microparticle Release in Human Vascular Smooth Muscle Cells","volume":"110","author":"Llampayas","year":"2004","journal-title":"Circulation"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14852","DOI":"10.1074\/jbc.M115.638361","article-title":"K Domain CR9 of Low Density Lipoprotein (LDL) Receptor-Related Protein 1 (LRP1) Is Critical for Aggregated LDL-Induced Foam Cell Formation from Human Vascular Smooth Muscle Cells","volume":"290","author":"Costales","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_72","first-page":"375","article-title":"Is Oxidized Low Density Lipoprotein Involved in the Recruitment and Retention of Monocyte\/Macrophages in the Artery Wall during the Initiation of Atherosclerosis?","volume":"49","author":"Parthasarathy","year":"1988","journal-title":"Basic Life Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11010-014-2259-0","article-title":"Lipopolysaccharide Augments the Uptake of Oxidized LDL by Up-Regulating Lectin-like Oxidized LDL Receptor-1 in Macrophages","volume":"400","author":"Hossain","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1093\/cvr\/cvy079","article-title":"PCSK9 Regulates Expression of Scavenger Receptors and Ox-LDL Uptake in Macrophages","volume":"114","author":"Ding","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.plipres.2011.04.002","article-title":"Cytokines, Macrophage Lipid Metabolism and Foam Cells: Implications for Cardiovascular Disease Therapy","volume":"50","author":"McLaren","year":"2011","journal-title":"Prog. Lipid Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1161\/01.ATV.0000249641.96896.e6","article-title":"Macrophage Low-Density Lipoprotein Receptor-Related Protein Deficiency Enhances Atherosclerosis in ApoE\/LDLR Double Knockout Mice","volume":"26","author":"Hu","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/j.bbadis.2014.05.009","article-title":"Apolipoprotein E Receptor-2 Deficiency Enhances Macrophage Susceptibility to Lipid Accumulation and Cell Death to Augment Atherosclerotic Plaque Progression and Necrosis","volume":"1842","author":"Waltmann","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.atherosclerosis.2018.07.014","article-title":"Role of Inflammation in the Pathogenesis of Atherosclerosis and Therapeutic Interventions","volume":"276","author":"Raggi","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/nature08938","article-title":"NLRP3 Inflammasomes Are Required for Atherogenesis and Activated by Cholesterol Crystals","volume":"464","author":"Duewell","year":"2010","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1161\/CIRCRESAHA.118.311362","article-title":"NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis","volume":"122","author":"Grebe","year":"2018","journal-title":"Circ. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.3892\/mmr.2017.6803","article-title":"Investigation of Highly Expressed PCSK9 in Atherosclerotic Plaques and Ox-LDL-Induced Endothelial Cell Apoptosis","volume":"16","author":"Li","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1194\/jlr.M051326","article-title":"Alirocumab Inhibits Atherosclerosis, Improves the Plaque Morphology, and Enhances the Effects of a Statin","volume":"55","author":"Pieterman","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1038\/s41598-018-20425-x","article-title":"PCSK9 Induces a Pro-Inflammatory Response in Macrophages","volume":"8","author":"Ricci","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1194\/jlr.M078360","article-title":"PCSK9 Deficiency Reduces Atherosclerosis, Apolipoprotein B Secretion, and Endothelial Dysfunction","volume":"59","author":"Sun","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1016\/j.jacc.2007.02.059","article-title":"Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior","volume":"49","author":"Chatzizisis","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1093\/cvr\/cvz262","article-title":"Blood Flow Patterns Regulate PCSK9 Secretion via MyD88-Mediated pro-Inflammatory Cytokines","volume":"116","author":"Liu","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/labinvest.2017.47","article-title":"Accelerated Atherosclerosis Development in C57Bl6 Mice by Overexpressing AAV-Mediated PCSK9 and Partial Carotid Ligation","volume":"97","author":"Kumar","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1161\/CIRCRESAHA.114.302937","article-title":"Induction of Atherosclerosis in Mice and Hamsters without Germline Genetic Engineering","volume":"114","author":"Hollensen","year":"2014","journal-title":"Circ. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.atherosclerosis.2015.09.008","article-title":"A Systematic Literature Review of the Effect of Carotid Atherosclerosis on Local Vessel Stiffness and Elasticity","volume":"243","author":"Boesen","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.jacl.2018.02.004","article-title":"Improved Endothelial Function after Short-Term Therapy with Evolocumab","volume":"12","author":"Maulucci","year":"2018","journal-title":"J. Clin. Lipidol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.numecd.2019.01.010","article-title":"Improvement in Arterial Stiffness after Short-Term Treatment with PCSK9 Inhibitors","volume":"29","author":"Cicero","year":"2019","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.atherosclerosis.2016.08.007","article-title":"PCSK9 and Atherosclerosis: Beyond LDL-Cholesterol Lowering","volume":"253","author":"Cariou","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"462","DOI":"10.5551\/jat.RV17003","article-title":"PCSK9 and Atherosclerosis\u2014Lipids and Beyond","volume":"24","author":"Shapiro","year":"2017","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1161\/CIRCULATIONAHA.115.018531","article-title":"Circulating Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors","volume":"133","author":"Leander","year":"2016","journal-title":"Circulation"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ijcard.2016.04.103","article-title":"Association between Plasma PCSK9 Levels and 10-Year Progression of Carotid Atherosclerosis beyond LDL-C: A Cohort Study","volume":"215","author":"Xie","year":"2016","journal-title":"Int J. Cardiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1161\/CIRCULATIONAHA.111.057406","article-title":"Gene Inactivation of Proprotein Convertase Subtilisin\/Kexin Type 9 Reduces Atherosclerosis in Mice","volume":"125","author":"Denis","year":"2012","journal-title":"Circulation"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s11883-014-0401-9","article-title":"Pathophysiology of Acute Coronary Syndrome","volume":"16","author":"Picatoste","year":"2014","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1161\/01.CIR.97.21.2110","article-title":"Effect of Risk Factors on the Mechanism of Acute Thrombosis and Sudden Coronary Death in Women","volume":"97","author":"Burke","year":"1998","journal-title":"Circulation"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1056\/NEJM199705013361802","article-title":"Coronary Risk Factors and Plaque Morphology in Men with Coronary Disease Who Died Suddenly","volume":"336","author":"Burke","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14360","DOI":"10.1038\/s41598-017-14307-x","article-title":"Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Deficiency Is Protective Against Venous Thrombosis in Mice","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1084\/jem.20112322","article-title":"Monocytes, Neutrophils, and Platelets Cooperate to Initiate and Propagate Venous Thrombosis in Mice In Vivo","volume":"209","author":"Stark","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil Extracellular Traps Kill Bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"15880","DOI":"10.1073\/pnas.1005743107","article-title":"Extracellular DNA Traps Promote Thrombosis","volume":"107","author":"Fuchs","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1038\/nm.2053","article-title":"Extracellular Histones Are Major Mediators of Death in Sepsis","volume":"15","author":"Xu","year":"2009","journal-title":"Nat. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.biopha.2018.09.164","article-title":"No Effect of PCSK9 Inhibitors on D-Dimer and Fibrinogen Levels in Patients with Familial Hypercholesterolemia","volume":"108","author":"Kruip","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1161\/01.ATV.0000259359.52265.62","article-title":"Platelet Adhesion Receptors and Their Ligands in Mouse Models of Thrombosis","volume":"27","author":"Denis","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Barale, C., and Russo, I. (2020). Influence of Cardiometabolic Risk Factors on Platelet Function. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020623"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41569-018-0110-0","article-title":"Platelet Biology and Functions: New Concepts and Clinical Perspectives","volume":"16","author":"Heemskerk","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/nm1626","article-title":"Platelet CD36 Links Hyperlipidemia, Oxidant Stress and a Prothrombotic Phenotype","volume":"13","author":"Podrez","year":"2007","journal-title":"Nat. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1161\/ATVBAHA.110.210252","article-title":"Deletion of the High-Density Lipoprotein Receptor Scavenger Receptor BI in Mice Modulates Thrombosis Susceptibility and Indirectly Affects Platelet Function by Elevation of Plasma Free Cholesterol","volume":"31","author":"Korporaal","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1161\/CIRCRESAHA.117.310795","article-title":"Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis","volume":"122","author":"Koupenova","year":"2018","journal-title":"Circ. Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.jacc.2017.11.069","article-title":"PCSK9 as a Positive Modulator of Platelet Activation","volume":"71","author":"Camera","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.ijcard.2016.10.084","article-title":"Association of PCSK9 with Platelet Reactivity in Patients with Acute Coronary Syndrome Treated with Prasugrel or Ticagrelor: The PCSK9-REACT Study","volume":"227","author":"Navarese","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.numecd.2019.09.012","article-title":"Platelet Function and Activation Markers in Primary Hypercholesterolemia Treated with Anti-PCSK9 Monoclonal Antibody: A 12-Month Follow-Up","volume":"30","author":"Barale","year":"2019","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Cammisotto, V., Pastori, D., Nocella, C., Bartimoccia, S., Castellani, V., Marchese, C., Scavalli, A.S., Ettorre, E., Viceconte, N., and Violi, F. (2020). PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation. Antioxidants, 9.","DOI":"10.3390\/antiox9040296"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"261","DOI":"10.7326\/0003-4819-158-4-201302190-00006","article-title":"Optimal Timing of Coronary Invasive Strategy in Non-ST-Segment Elevation Acute Coronary Syndromes: A Systematic Review and Meta-Analysis","volume":"158","author":"Navarese","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/09537109709169333","article-title":"Differential Effects of Native and Oxidatively Modified Low-Density Lipoproteins on Platelet Function","volume":"8","author":"Naseem","year":"1997","journal-title":"Platelets"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1161\/CIRCULATIONAHA.120.046290","article-title":"PCSK9 (Proprotein Convertase Subtilisin\/Kexin 9) Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36","volume":"143","author":"Qi","year":"2021","journal-title":"Circulation"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"76","DOI":"10.5551\/jat.25841","article-title":"The Relationship between the Plasma PCSK9 Levels and Platelet Indices in Patients with Stable Coronary Artery Disease","volume":"22","author":"Li","year":"2015","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1161\/01.CIR.84.2.613","article-title":"Blood Platelet Count and Function Are Related to Total and Cardiovascular Death in Apparently Healthy Men","volume":"84","author":"Thaulow","year":"1991","journal-title":"Circulation"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1538-7836.2008.03267.x","article-title":"Platelet Count and the Risk for Thrombosis and Death in the Elderly","volume":"7","author":"Heckbert","year":"2009","journal-title":"J. Thromb. Haemost."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.arr.2018.09.004","article-title":"Significance of Urinary 11-Dehydro-Thromboxane B2 in Age-Related Diseases: Focus on Atherothrombosis","volume":"48","author":"Simeone","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00018-003-2249-y","article-title":"Low-Density Lipoprotein and Its Effect on Human Blood Platelets","volume":"60","author":"Relou","year":"2003","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1152\/japplphysiol.00879.2009","article-title":"EGCG Protects against Oxidized LDL-Induced Endothelial Dysfunction by Inhibiting LOX-1-Mediated Signaling","volume":"108","author":"Ou","year":"2010","journal-title":"J. Appl. Physiol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.mam.2004.09.003","article-title":"The Role of Nitric Oxide in Cardiovascular Diseases","volume":"26","author":"Naseem","year":"2005","journal-title":"Mol. Aspects Med."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"6508709","DOI":"10.1155\/2018\/6508709","article-title":"Simvastatin Effects on Inflammation and Platelet Activation Markers in Hypercholesterolemia","volume":"2018","author":"Barale","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1161\/01.ATV.0000193622.77294.57","article-title":"Platelet Nitric Oxide Responsiveness: A Novel Prognostic Marker in Acute Coronary Syndromes","volume":"25","author":"Willoughby","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.atherosclerosis.2004.02.008","article-title":"Altered Platelet Reactivity in Peripheral Vascular Disease Complicated with Elevated Plasma Homocysteine Levels","volume":"175","author":"Riba","year":"2004","journal-title":"Atherosclerosis"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/oby.2009.302","article-title":"In Central Obesity, Weight Loss Restores Platelet Sensitivity to Nitric Oxide and Prostacyclin","volume":"18","author":"Russo","year":"2010","journal-title":"Obesity"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.thromres.2019.06.010","article-title":"Hypercholesterolemia Impairs the Glucagon-like Peptide 1 Action on Platelets: Effects of a Lipid-Lowering Treatment with Simvastatin","volume":"180","author":"Barale","year":"2019","journal-title":"Thromb. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"e285","DOI":"10.1016\/j.jacc.2018.11.003","article-title":"2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"73","author":"Grundy","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/eurheartj\/ehz455","article-title":"2019 ESC\/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk","volume":"41","author":"Mach","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1001\/jama.285.13.1711","article-title":"Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes: The MIRACL Study: A Randomized Controlled Trial","volume":"285","author":"Schwartz","year":"2001","journal-title":"JAMA"},{"key":"ref_134","first-page":"1476","article-title":"Ezetimibe plus a Statin after Acute Coronary Syndromes","volume":"373","author":"Cannon","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.atherosclerosis.2018.06.871","article-title":"Lipid Management in ACS: Should We Go Lower Faster?","volume":"275","author":"Gencer","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.thromres.2020.07.049","article-title":"Endothelial Function Improvement in Patients with Familial Hypercholesterolemia Receiving PCSK-9 Inhibitors on Top of Maximally Tolerated Lipid Lowering Therapy","volume":"194","author":"Gentile","year":"2020","journal-title":"Thromb. Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.numecd.2020.02.018","article-title":"Changes in Carotid Stiffness in Patients with Familial Hypercholesterolemia Treated with Evolocumab\u00ae: A Prospective Cohort Study","volume":"30","author":"Gentile","year":"2020","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.diabet.2017.07.009","article-title":"Circulating PCSK9 Levels in Acute Coronary Syndrome: Results from the PC-SCA-9 Prospective Study","volume":"43","author":"Cariou","year":"2017","journal-title":"Diabetes Metab."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1097\/SHK.0000000000000682","article-title":"Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis","volume":"46","author":"Dwivedi","year":"2016","journal-title":"Shock"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"258ra143","DOI":"10.1126\/scitranslmed.3008782","article-title":"PCSK9 Is a Critical Regulator of the Innate Immune Response and Septic Shock Outcome","volume":"6","author":"Walley","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2784","DOI":"10.1182\/blood-2013-04-457671","article-title":"NETosis: How Vital Is It?","volume":"122","author":"Yipp","year":"2013","journal-title":"Blood"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1161\/ATVBAHA.111.242859","article-title":"Neutrophil Extracellular Trap (NET) Impact on Deep Vein Thrombosis","volume":"32","author":"Fuchs","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1097\/SHK.0000000000000397","article-title":"Comparison of the Proinflammatory and Procoagulant Properties of Nuclear, Mitochondrial, and Bacterial DNA","volume":"44","author":"Bhagirath","year":"2015","journal-title":"Shock"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1161\/ATVBAHA.114.304114","article-title":"Neutrophil Extracellular Traps Promote Thrombin Generation through Platelet-Dependent and Platelet-Independent Mechanisms","volume":"34","author":"Gould","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1161\/ATVBAHA.115.306035","article-title":"Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis","volume":"35","author":"Gould","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1111\/j.1538-7836.2011.04465.x","article-title":"Breast Cancer Chemotherapy Induces the Release of Cell-Free DNA, a Novel Procoagulant Stimulus","volume":"9","author":"Swystun","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0009-8981(02)00337-6","article-title":"Elevated Cell-Free Serum DNA Detected in Patients with Myocardial Infarction","volume":"327","author":"Chang","year":"2003","journal-title":"Clin. Chim. Acta"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1097\/SHK.0b013e31816a6bb1","article-title":"Neutrophil-Derived Circulating Free DNA (Cf-DNA\/NETs): A Potential Prognostic Marker for Posttraumatic Development of Inflammatory Second Hit and Sepsis","volume":"30","author":"Margraf","year":"2008","journal-title":"Shock"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41569-018-0098-5","article-title":"Safety and Efficacy of Statin Therapy","volume":"15","author":"Adhyaru","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/S2213-8587(19)30388-2","article-title":"Intensive LDL Cholesterol-Lowering Treatment beyond Current Recommendations for the Prevention of Major Vascular Events: A Systematic Review and Meta-Analysis of Randomised Trials Including 327\u2008037 Participants","volume":"8","author":"Wang","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.jacl.2017.09.003","article-title":"Long-Term Safety, Tolerability, and Efficacy of Evolocumab in Patients with Heterozygous Familial Hypercholesterolemia","volume":"11","author":"Hovingh","year":"2017","journal-title":"J. Clin. Lipidol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/jca.21632","article-title":"Evolocumab and Lipoprotein Apheresis Combination Therapy May Have Synergic Effects to Reduce Low-Density Lipoprotein Cholesterol Levels in Heterozygous Familial Hypercholesterolemia: A Case Report","volume":"33","author":"Zenti","year":"2018","journal-title":"J. Clin. Apher."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jacl.2017.12.008","article-title":"Alirocumab Efficacy in Patients with Double Heterozygous, Compound Heterozygous, or Homozygous Familial Hypercholesterolemia","volume":"12","author":"Hartgers","year":"2018","journal-title":"J. Clin. Lipidol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"e177","DOI":"10.1016\/j.jacc.2019.03.010","article-title":"2019 ACC\/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"74","author":"Arnett","year":"2019","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","article-title":"Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease","volume":"376","author":"Sabatine","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1056\/NEJMoa1801174","article-title":"Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome","volume":"379","author":"Schwartz","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/S2213-8587(17)30313-3","article-title":"Cardiovascular Safety and Efficacy of the PCSK9 Inhibitor Evolocumab in Patients with and without Diabetes and the Effect of Evolocumab on Glycaemia and Risk of New-Onset Diabetes: A Prespecified Analysis of the FOURIER Randomised Controlled Trial","volume":"5","author":"Sabatine","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1001\/jamacardio.2020.3151","article-title":"Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial","volume":"6","author":"Deedwania","year":"2021","journal-title":"JAMA Cardiol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1161\/STROKEAHA.119.027759","article-title":"Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis","volume":"51","author":"Giugliano","year":"2020","journal-title":"Stroke"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1161\/CIRCULATIONAHA.119.043805","article-title":"Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial","volume":"141","author":"Marston","year":"2020","journal-title":"Circulation"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1161\/CIRCULATIONAHA.119.044434","article-title":"Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial","volume":"141","author":"Damask","year":"2020","journal-title":"Circulation"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1161\/CIRCULATIONAHA.120.046397","article-title":"The Effect of PCSK9 (Proprotein Convertase Subtilisin\/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism","volume":"141","author":"Marston","year":"2020","journal-title":"Circulation"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2459\/JCM.0000000000000611","article-title":"Adherence to Proprotein Convertase Subtilisin\/Kexin 9 Inhibitors in High Cardiovascular Risk Patients: An Italian Single-Center Experience","volume":"19","author":"Gragnano","year":"2018","journal-title":"J. Cardiovasc. Med."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1177\/2047487319839179","article-title":"Impact of PCSK9 Inhibitors on the Quality of Life of Patients at High Cardiovascular Risk","volume":"27","author":"Cesaro","year":"2020","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.2147\/PPA.S149423","article-title":"Patient Adherence, Compliance, and Perspectives on Evolocumab for the Management of Resistant Hypercholesterolemia","volume":"12","author":"Kosmas","year":"2018","journal-title":"Patient Prefer. Adherence"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/13543784.2018.1442435","article-title":"Inclisiran for the Treatment of Dyslipidemia","volume":"27","author":"Nishikido","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1609243","article-title":"A Highly Durable RNAi Therapeutic Inhibitor of PCSK9","volume":"376","author":"Fitzgerald","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1056\/NEJMoa1913805","article-title":"Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia","volume":"382","author":"Raal","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s40265-021-01473-6","article-title":"Inclisiran: First Approval","volume":"81","author":"Lamb","year":"2021","journal-title":"Drugs"},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Rothgangl, T., Dennis, M.K., Lin, P.J.C., Oka, R., Witzigmann, D., Villiger, L., Qi, W., Hruzova, M., Kissling, L., and Lenggenhager, D. (2021). In Vivo Adenine Base Editing of PCSK9 in Macaques Reduces LDL Cholesterol Levels. Nat. Biotechnol.","DOI":"10.1038\/s41587-021-00933-4"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41586-021-03534-y","article-title":"In Vivo CRISPR Base Editing of PCSK9 Durably Lowers Cholesterol in Primates","volume":"593","author":"Musunuru","year":"2021","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5880\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:11Z","timestamp":1760162951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,30]]},"references-count":171,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115880"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115880","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,30]]}}}