{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:11:56Z","timestamp":1780791116044,"version":"3.54.1"},"reference-count":46,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T00:00:00Z","timestamp":1634342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["374031971"],"award-info":[{"award-number":["374031971"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["335549539"],"award-info":[{"award-number":["335549539"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Platelets play a significant role in atherothrombosis. Proprotein convertase subtilisin\/kexin type 9 (PCSK9) is critically involved in the regulation of LDL metabolism and interacts with platelet function. The effect of PCSK9 in platelet function is poorly understood. The authors of this article sought to characterize platelets as a major source of PCSK9 and PCSK9\u2019s role in atherothrombosis. In a large cohort of patients with coronary artery disease (CAD), platelet count, platelet reactivity, and platelet-derived PCSK9 release were analyzed. The role of platelet PCSK9 on platelet and monocyte function was investigated in vitro. Platelet count and hyper-reactivity correlated with plasma LDL in CAD. The circulating platelets express on their surface and release substantial amounts of PCSK9. Release of PCSK9 augmented platelet-dependent thrombosis, monocyte migration, and differentiation into macrophages\/foam cells. Platelets and PCSK9 accumulated in tissue derived from atherosclerotic carotid arteries in areas of macrophages. PCSK9 inhibition reduced platelet activation and platelet-dependent thrombo-inflammation. The authors identified platelets as a source of PCSK9 in CAD, which may have an impact on LDL metabolism. Furthermore, platelet-derived PCSK9 contributes to atherothrombosis, and inhibition of PCSK9 attenuates thrombo-inflammation, which may contribute to the reported beneficial clinical effects.<\/jats:p>","DOI":"10.3390\/ijms222011179","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T23:05:47Z","timestamp":1634511947000},"page":"11179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Platelet-Derived PCSK9 Is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"\u00c1lvaro","family":"Petersen-Uribe","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-3438","authenticated-orcid":false,"given":"Marcel","family":"Kremser","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5469-3648","authenticated-orcid":false,"given":"Anne-Katrin","family":"Rohlfing","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsiana","family":"Castor","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4034-744X","authenticated-orcid":false,"given":"Kyra","family":"Kolb","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-4102","authenticated-orcid":false,"given":"Valerie","family":"Dicenta","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Emschermann","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Borst","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Rath","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin Anne Lydia","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1124-9592","authenticated-orcid":false,"given":"Meinrad Paul","family":"Gawaz","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1172\/JCI27196","article-title":"Platelets in inflammation and atherogenesis","volume":"115","author":"Gawaz","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.cardiores.2003.11.036","article-title":"Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium","volume":"61","author":"Gawaz","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1084\/jem.20012044","article-title":"A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation","volume":"196","author":"Massberg","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.2217\/14622416.9.9.1251","article-title":"CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation","volume":"9","author":"Geisler","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref_5","first-page":"203","article-title":"Increased fibrinogen binding to platelets from patients with familial hypercholesterolemia","volume":"6","author":"DiMinno","year":"1986","journal-title":"Arter. Off. J. Am. Heart Assoc. Inc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1093\/eurheartj\/ehx146","article-title":"Regulation of oxidized platelet lipidome: Implications for coronary artery disease","volume":"38","author":"Chatterjee","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1182\/blood-2014-05-574491","article-title":"Oxidized LDL activates blood platelets through CD36\/NOX2\u2013mediated inhibition of the cGMP\/protein kinase G signaling cascade","volume":"125","author":"Magwenzi","year":"2015","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e13459","DOI":"10.1111\/eci.13459","article-title":"PCSK9 and atherosclerosis: Looking beyond LDL regulation","volume":"51","author":"Ragusa","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00395-017-0619-0","article-title":"Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease","volume":"112","author":"Glerup","year":"2017","journal-title":"Basic Res. Cardiol."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1055\/s-0038-1676863","article-title":"PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention","volume":"119","author":"Paciullo","year":"2019","journal-title":"Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.ajpath.2021.04.016","article-title":"Proprotein Convertase Subtilisin Kexin Type 9","volume":"191","author":"Macchi","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.jacc.2013.07.056","article-title":"Targeting the Proprotein Convertase Subtilisin\/Kexin Type 9 for the Treatment of Dyslipidemia and Atherosclerosis","volume":"62","author":"Urban","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3389\/fnagi.2019.00120","article-title":"Proprotein Convertase Subtilisin\/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer\u2019s Disease","volume":"11","author":"Adorni","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_16","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_17","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_18","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_19","doi-asserted-by":"crossref","unstructured":"Cammisotto, V., Baratta, F., Castellani, V., Bartimoccia, S., Nocella, C., D\u2019Erasmo, L., Cocomello, N., Barale, C., Scicali, R., and Di Pino, A. (2021). Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137193"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1056\/NEJMoa1912387","article-title":"Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol","volume":"382","author":"Ray","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_22","first-page":"1353","article-title":"LDL binding sites on platelets differ from the \u201cclassical\u201d receptor of nucleated cells","volume":"12","year":"1992","journal-title":"Arter. Thromb. A J. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1093\/cvr\/cvaa080","article-title":"The chemokine CXCL14 mediates platelet function and migration via direct interaction with CXCR4","volume":"117","author":"Witte","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41591-019-0379-5","article-title":"Platelet GPIb\u03b1 is a mediator and potential interventional target for NASH and subsequent liver cancer","volume":"25","author":"Malehmir","year":"2019","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1093\/eurheartj\/eht448","article-title":"Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery","volume":"35","author":"Rath","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1096\/fj.06-6265fje","article-title":"Platelets induce differentiation of human CD34 + progenitor cells into foam cells and endothelial cells","volume":"20","author":"Daub","year":"2006","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s00109-010-0629-y","article-title":"Inhibition of foam cell formation using a soluble CD68-Fc fusion protein","volume":"88","author":"Daub","year":"2010","journal-title":"J. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"31635","DOI":"10.1074\/jbc.M113.477745","article-title":"Gremlin-1 Is an Inhibitor of Macrophage Migration Inhibitory Factor and Attenuates Atherosclerotic Plaque Growth in ApoE\u2212\/\u2212 Mice","volume":"288","author":"Schneider","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e1989","DOI":"10.1038\/cddis.2015.233","article-title":"Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4\u2013CXCR7","volume":"6","author":"Chatterjee","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.atherosclerosis.2009.08.029","article-title":"EMMPRIN and its ligand cyclophilin A regulate MT1-MMP, MMP-9 and M-CSF during foam cell formation","volume":"209","author":"Seizer","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.jacc.2018.04.054","article-title":"The Evolving Future of PCSK9 Inhibitors","volume":"72","author":"Rosenson","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_32","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_33","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.jacc.2017.07.745","article-title":"2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk","volume":"70","author":"Morris","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.vph.2014.03.004","article-title":"Risk prediction with proprotein convertase subtilisin\/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment","volume":"62","author":"Werner","year":"2014","journal-title":"Vasc. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1161\/ATVBAHA.115.306172","article-title":"Association of Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) With Cardiovascular Risk in Primary Prevention","volume":"35","author":"Zhu","year":"2015","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1093\/eurheartj\/ehv568","article-title":"Plasma proprotein convertase subtilisin\/kexin type 9 levels and the risk of first cardiovascular events","volume":"37","author":"Ridker","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1093\/eurheartj\/ehv637","article-title":"Prognostic value of PCSK9 levels in patients with acute coronary syndromes","volume":"37","author":"Gencer","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1177\/2047487318815320","article-title":"Long-term exposure to air pollution raises circulating levels of proprotein convertase subtilisin\/kexin type 9 in obese individuals","volume":"26","author":"Macchi","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1001\/jama.2016.16951","article-title":"Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients","volume":"316","author":"Nicholls","year":"2016","journal-title":"JAMA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.atherosclerosis.2016.03.010","article-title":"PCSK9 in relation to coronary plaque inflammation: Results of the ATHEROREMO-IVUS study","volume":"248","author":"Cheng","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/biof.1619","article-title":"Beyond cholesterol metabolism: The pleiotropic effects of proprotein convertase subtilisin\/kexin type 9 (PCSK9). Genetics, mutations, expression, and perspective for long-term inhibition","volume":"46","author":"Cesaro","year":"2020","journal-title":"BioFactors"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1182\/blood.2019000185","article-title":"Pivotal role of PDK1 in megakaryocyte cytoskeletal dynamics and polarization during platelet biogenesis","volume":"134","author":"Geue","year":"2019","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1161\/ATVBAHA.115.307105","article-title":"PDK1 Determines Collagen-Dependent Platelet Ca 2+ Signaling and Is Critical to Development of Ischemic Stroke In Vivo","volume":"36","author":"Geue","year":"2016","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1182\/bloodadvances.2017013573","article-title":"Inhibitory mechanisms of very low\u2013dose rivaroxaban in non\u2013ST-elevation myocardial infarction","volume":"2","author":"Borst","year":"2018","journal-title":"Blood Adv."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11179\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:16:16Z","timestamp":1760166976000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,16]]},"references-count":46,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011179"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011179","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,16]]}}}