{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:51:53Z","timestamp":1791363113973,"version":"4.3.1"},"reference-count":112,"publisher":"Elsevier BV","issue":"8","license":[{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":365,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2018-0511"],"award-info":[{"award-number":["2018-0511"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ajp.amjpathol.org","clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The American Journal of Pathology"],"published-print":{"date-parts":[[2021,8]]},"DOI":"10.1016\/j.ajpath.2021.04.016","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:02:59Z","timestamp":1621382579000},"page":"1385-1397","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":86,"title":["Proprotein Convertase Subtilisin\/Kexin Type 9"],"prefix":"10.1016","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5919-989X","authenticated-orcid":false,"given":"Chiara","family":"Macchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-7441","authenticated-orcid":false,"given":"Nicola","family":"Ferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6224-5538","authenticated-orcid":false,"given":"Cesare R.","family":"Sirtori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Corsini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Banach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0195-7061","authenticated-orcid":false,"given":"Massimiliano","family":"Ruscica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ajpath.2021.04.016_bib1","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":"10.1016\/j.ajpath.2021.04.016_bib2","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":"10.1016\/j.ajpath.2021.04.016_bib3","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/hep.22354","article-title":"Proprotein convertase subtilisin\/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration","volume":"48","author":"Zaid","year":"2008","journal-title":"Hepatology"},{"key":"10.1016\/j.ajpath.2021.04.016_bib4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/dom.13636","article-title":"Efficacy and safety of proprotein convertase subtilisin\/kexin 9 inhibitors in people with diabetes and dyslipidaemia","volume":"21 Suppl 1","author":"Dijk","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"10.1016\/j.ajpath.2021.04.016_bib5","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 U S A"},{"key":"10.1016\/j.ajpath.2021.04.016_bib6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.jmb.2004.10.050","article-title":"Than ME: Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity","volume":"345","author":"Henrich","year":"2005","journal-title":"J Mol Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib7","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nsmb1235","article-title":"Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia","volume":"14","author":"Cunningham","year":"2007","journal-title":"Nat Struct Mol Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib8","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.abb.2003.09.011","article-title":"Functional characterization of Narc 1, a novel proteinase related to proteinase K","volume":"420","author":"Naureckiene","year":"2003","journal-title":"Arch Biochem Biophys"},{"key":"10.1016\/j.ajpath.2021.04.016_bib9","doi-asserted-by":"crossref","first-page":"43492","DOI":"10.1074\/jbc.M112.394023","article-title":"The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway","volume":"287","author":"Saavedra","year":"2012","journal-title":"J Biol Chem"},{"key":"10.1016\/j.ajpath.2021.04.016_bib10","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1194\/jlr.M018093","article-title":"Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors","volume":"52","author":"Holla","year":"2011","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib11","doi-asserted-by":"crossref","first-page":"18602","DOI":"10.1074\/jbc.M702027200","article-title":"Binding of proprotein convertase subtilisin\/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation","volume":"282","author":"Zhang","year":"2007","journal-title":"J Biol Chem"},{"key":"10.1016\/j.ajpath.2021.04.016_bib12","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":"10.1016\/j.ajpath.2021.04.016_bib13","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":"10.1016\/j.ajpath.2021.04.016_bib14","doi-asserted-by":"crossref","first-page":"C1082","DOI":"10.1152\/ajpcell.00244.2019","article-title":"Hydrogen sulfide accumulates LDL receptor precursor via downregulating PCSK9 in HepG2 cells","volume":"319","author":"Huang","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib15","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 U S A"},{"key":"10.1016\/j.ajpath.2021.04.016_bib16","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1194\/jlr.M041129","article-title":"Characterization of the role of EGF-A of low density lipoprotein receptor in PCSK9 binding","volume":"54","author":"Gu","year":"2013","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib17","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1161\/ATVBAHA.115.306032","article-title":"PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver","volume":"35","author":"Demers","year":"2015","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib18","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.trsl.2015.10.004","article-title":"Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: experimental animal models and clinical evidence","volume":"173","author":"Ferri","year":"2016","journal-title":"Transl Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib19","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1172\/JCI29383","article-title":"Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice","volume":"116","author":"Lagace","year":"2006","journal-title":"J Clin Invest"},{"key":"10.1016\/j.ajpath.2021.04.016_bib20","doi-asserted-by":"crossref","first-page":"100003","DOI":"10.1194\/jlr.RA120000964","article-title":"Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9","volume":"62","author":"Oleaga","year":"2020","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib21","doi-asserted-by":"crossref","first-page":"e00444","DOI":"10.7554\/eLife.00444","article-title":"SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion","volume":"2","author":"Chen","year":"2013","journal-title":"eLife"},{"key":"10.1016\/j.ajpath.2021.04.016_bib22","doi-asserted-by":"crossref","first-page":"158660","DOI":"10.1016\/j.bbalip.2020.158660","article-title":"The role of the C-terminal domain of PCSK9 and SEC24 isoforms in PCSK9 secretion","volume":"1865","author":"Deng","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"10.1016\/j.ajpath.2021.04.016_bib23","doi-asserted-by":"crossref","first-page":"e38839","DOI":"10.7554\/eLife.38839","article-title":"The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9","volume":"7","author":"Emmer","year":"2018","journal-title":"Elife"},{"key":"10.1016\/j.ajpath.2021.04.016_bib24","doi-asserted-by":"crossref","first-page":"158555","DOI":"10.1016\/j.bbalip.2019.158555","article-title":"Surf4 regulates expression of proprotein convertase subtilisin\/kexin type 9 (PCSK9) but is not required for PCSK9 secretion in cultured human hepatocytes","volume":"1865","author":"Shen","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"10.1016\/j.ajpath.2021.04.016_bib25","doi-asserted-by":"crossref","DOI":"10.1093\/cvr\/cvab034","article-title":"Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion","author":"Rogers","year":"2021","journal-title":"Cardiovasc Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib26","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.cmet.2013.12.006","article-title":"The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion","volume":"19","author":"Gustafsen","year":"2014","journal-title":"Cell Metab"},{"key":"10.1016\/j.ajpath.2021.04.016_bib27","doi-asserted-by":"crossref","first-page":"12027","DOI":"10.1073\/pnas.1534923100","article-title":"Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes","volume":"100","author":"Horton","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.ajpath.2021.04.016_bib28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1194\/jlr.M700443-JLR200","article-title":"Sterol-dependent regulation of proprotein convertase subtilisin\/kexin type 9 expression by sterol-regulatory element binding protein-2","volume":"49","author":"Jeong","year":"2008","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib29","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1194\/jlr.M003566","article-title":"Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters","volume":"51","author":"Dong","year":"2010","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib30","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1172\/JCI61919","article-title":"Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice","volume":"122","author":"Ai","year":"2012","journal-title":"J Clin Invest"},{"key":"10.1016\/j.ajpath.2021.04.016_bib31","doi-asserted-by":"crossref","first-page":"e208","DOI":"10.1161\/ATVBAHA.120.315708","article-title":"New insight into metformin-induced cholesterol-lowering effect crosstalk between glucose and cholesterol homeostasis via ChREBP (carbohydrate-responsive element-binding protein)-mediated PCSK9 (proprotein convertase subtilisin\/kexin type 9) regulation","volume":"41","author":"Hu","year":"2021","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib32","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1515\/BC.2009.035","article-title":"Central nervous system: cholesterol turnover, brain development and neurodegeneration","volume":"390","author":"Dietschy","year":"2009","journal-title":"Biol Chem"},{"key":"10.1016\/j.ajpath.2021.04.016_bib33","doi-asserted-by":"crossref","first-page":"609","DOI":"10.3389\/fnins.2020.00609","article-title":"Proprotein convertase subtilisin\/kexin type 9 (PCSK9) in the brain and relevance for neuropsychiatric disorders","volume":"14","author":"O'Connell","year":"2020","journal-title":"Front Neurosci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib34","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1111\/j.1471-4159.2006.03928.x","article-title":"Implication of the proprotein convertase NARC-1\/PCSK9 in the development of the nervous system","volume":"98","author":"Poirier","year":"2006","journal-title":"J Neurochem"},{"key":"10.1016\/j.ajpath.2021.04.016_bib35","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1194\/jlr.M014118","article-title":"PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke","volume":"52","author":"Rousselet","year":"2011","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib36","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.neures.2007.07.004","article-title":"LDL receptor deficiency results in decreased cell proliferation and presynaptic bouton density in the murine hippocampus","volume":"59","author":"Mulder","year":"2007","journal-title":"Neurosci Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib37","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.neuron.2009.11.013","article-title":"Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance","volume":"64","author":"Kim","year":"2009","journal-title":"Neuron"},{"key":"10.1016\/j.ajpath.2021.04.016_bib38","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's disease","volume":"11","author":"Adorni","year":"2019","journal-title":"Front Aging Neurosci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib39","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/embor.2008.132","article-title":"PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1","volume":"9","author":"Jonas","year":"2008","journal-title":"EMBO Rep"},{"key":"10.1016\/j.ajpath.2021.04.016_bib40","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1194\/jlr.M006635","article-title":"PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain","volume":"51","author":"Liu","year":"2010","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib41","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1002\/ana.25642","article-title":"Lipid lowering and Alzheimer disease risk: a mendelian randomization study","volume":"87","author":"Williams","year":"2020","journal-title":"Ann Neurol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib42","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1016\/j.ajpath.2019.04.010","article-title":"Apolipoprotein E\/amyloid-beta complex accumulates in Alzheimer disease cortical synapses via apolipoprotein E receptors and is enhanced by APOE4","volume":"189","author":"Bilousova","year":"2019","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib43","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3233\/JAD-160411","article-title":"Increased PCSK9 cerebrospinal fluid concentrations in Alzheimer's disease","volume":"55","author":"Zimetti","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"10.1016\/j.ajpath.2021.04.016_bib44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.5114\/aoms\/127226","article-title":"PCSK9 genetic variants and cognitive abilities: a large-scale Mendelian randomization study","volume":"17","author":"Lyall","year":"2021","journal-title":"Arch Med Sci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib45","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1016\/j.jacc.2020.03.039","article-title":"Cognition after lowering LDL-cholesterol with evolocumab","volume":"75","author":"Gencer","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib46","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s40264-020-01021-3","article-title":"PCSK9 inhibitors and neurocognitive adverse drug reactions: analysis of individual case safety reports from the eudravigilance database","volume":"44","author":"di Mauro","year":"2021","journal-title":"Drug Saf"},{"key":"10.1016\/j.ajpath.2021.04.016_bib47","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s12933-020-01158-6","article-title":"Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance","volume":"19","author":"Macchi","year":"2020","journal-title":"Cardiovasc Diabetol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib48","doi-asserted-by":"crossref","first-page":"e002196","DOI":"10.1161\/CIRCGEN.118.002196","article-title":"Genetic assessment of potential long-term on-target side effects of PCSK9 (proprotein convertase subtilisin\/kexin type 9) inhibitors","volume":"12","author":"Nelson","year":"2019","journal-title":"Circ Genom Precis Med"},{"key":"10.1016\/j.ajpath.2021.04.016_bib49","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1074\/jbc.M407167200","article-title":"Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein","volume":"280","author":"Kruth","year":"2005","journal-title":"J Biol Chem"},{"key":"10.1016\/j.ajpath.2021.04.016_bib50","article-title":"PCSK9 and LRP5 in macrophage lipid internalization and inflammation","author":"Badimon","year":"2020","journal-title":"Cardiovasc Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib51","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":"10.1016\/j.ajpath.2021.04.016_bib52","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":"10.1016\/j.ajpath.2021.04.016_bib53","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":"10.1016\/j.ajpath.2021.04.016_bib54","doi-asserted-by":"crossref","first-page":"e016263","DOI":"10.1161\/JAHA.120.016263","article-title":"Evolocumab, a PCSK9-monoclonal antibody, rapidly reverses coronary artery endothelial dysfunction in people living with HIV and people with dyslipidemia","volume":"9","author":"Leucker","year":"2020","journal-title":"J Am Heart Assoc"},{"key":"10.1016\/j.ajpath.2021.04.016_bib55","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/path.4630","article-title":"Local effects of human PCSK9 on the atherosclerotic lesion","volume":"238","author":"Giunzioni","year":"2016","journal-title":"J Pathol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib56","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":"10.1016\/j.ajpath.2021.04.016_bib57","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.atherosclerosis.2017.04.023","article-title":"New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4\/NF-kappaB pathway","volume":"262","author":"Tang","year":"2017","journal-title":"Atherosclerosis"},{"key":"10.1016\/j.ajpath.2021.04.016_bib58","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":"10.1016\/j.ajpath.2021.04.016_bib59","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":"10.1016\/j.ajpath.2021.04.016_bib60","doi-asserted-by":"crossref","first-page":"113863","DOI":"10.1016\/j.bcp.2020.113863","article-title":"Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators","volume":"175","author":"Liu","year":"2020","journal-title":"Biochem Pharmacol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib61","first-page":"389","article-title":"Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities","volume":"16","author":"Back","year":"2019","journal-title":"Nat Rev Cardiol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib62","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.atherosclerosis.2019.07.015","article-title":"PCSK9 inhibition and inflammation: a narrative review","volume":"288","author":"Ruscica","year":"2019","journal-title":"Atherosclerosis"},{"key":"10.1016\/j.ajpath.2021.04.016_bib63","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":"10.1016\/j.ajpath.2021.04.016_bib64","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.7150\/thno.45939","article-title":"NLRP3 inflammasome via IL-1beta regulates PCSK9 secretion","volume":"10","author":"Ding","year":"2020","journal-title":"Theranostics"},{"key":"10.1016\/j.ajpath.2021.04.016_bib65","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":"Kuhnast","year":"2014","journal-title":"J Lipid Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib66","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1093\/eurheartj\/ehx260","article-title":"The AT04A vaccine against proprotein convertase subtilisin\/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE\u22173Leiden.CETP mice","volume":"38","author":"Landlinger","year":"2017","journal-title":"Eur Heart J"},{"key":"10.1016\/j.ajpath.2021.04.016_bib67","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s10557-020-07041-6","article-title":"PCSK9Qbeta-003 vaccine attenuates atherosclerosis in apolipoprotein E-deficient mice","volume":"35","author":"Wu","year":"2021","journal-title":"Cardiovasc Drugs Ther"},{"key":"10.1016\/j.ajpath.2021.04.016_bib68","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1161\/01.ATV.0000133684.77013.88","article-title":"Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9","volume":"24","author":"Ouguerram","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib69","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.tem.2018.03.013","article-title":"Beyond LDL: what role for PCSK9 in triglyceride-rich lipoprotein metabolism?","volume":"29","author":"Dijk","year":"2018","journal-title":"Trends Endocrinol Metab"},{"key":"10.1016\/j.ajpath.2021.04.016_bib70","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1210\/en.2006-0098","article-title":"Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor","volume":"147","author":"Lambert","year":"2006","journal-title":"Endocrinology"},{"key":"10.1016\/j.ajpath.2021.04.016_bib71","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":"10.1016\/j.ajpath.2021.04.016_bib72","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1161\/ATVBAHA.110.204040","article-title":"Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control","volume":"30","author":"Herbert","year":"2010","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib73","doi-asserted-by":"crossref","first-page":"e13471","DOI":"10.1111\/eci.13471","article-title":"Endogenous fibrinolysis-relevance to clinical thrombosis risk assessment","volume":"51","author":"Kanji","year":"2020","journal-title":"Eur J Clin Invest"},{"key":"10.1016\/j.ajpath.2021.04.016_bib74","doi-asserted-by":"crossref","first-page":"604","DOI":"10.5603\/CJ.a2016.0068","article-title":"Evaluation of plasma PCSK9 concentrations, transcript of LDL receptor, as well as the total number of monocyte LDL receptors in acute coronary syndrome patients","volume":"23","author":"Burchardt","year":"2016","journal-title":"Cardiol J"},{"key":"10.1016\/j.ajpath.2021.04.016_bib75","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":"10.1016\/j.ajpath.2021.04.016_bib76","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":"10.1016\/j.ajpath.2021.04.016_bib77","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":"10.1016\/j.ajpath.2021.04.016_bib78","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":"10.1016\/j.ajpath.2021.04.016_bib79","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":"10.1016\/j.ajpath.2021.04.016_bib80","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/MOL.0000000000000180","article-title":"Role of PCSK9 beyond liver involvement","volume":"26","author":"Cariou","year":"2015","journal-title":"Curr Opin Lipidol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib81","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1161\/ATVBAHA.108.181586","article-title":"Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia","volume":"29","author":"Le May","year":"2009","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib82","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1161\/ATVBAHA.120.314194","article-title":"Circulating rather than intestinal PCSK9 (proprotein convertase subtilisin kexin type 9) regulates postprandial lipemia in mice","volume":"40","author":"Garcon","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib83","doi-asserted-by":"crossref","first-page":"3452","DOI":"10.1210\/jc.2017-00684","article-title":"The effect of PCSK9 loss-of-function variants on the postprandial lipid and ApoB-lipoprotein response","volume":"102","author":"Ooi","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"10.1016\/j.ajpath.2021.04.016_bib84","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":"10.1016\/j.ajpath.2021.04.016_bib85","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":"10.1016\/j.ajpath.2021.04.016_bib86","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1161\/ATVBAHA.112.300263","article-title":"Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1","volume":"33","author":"Le May","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib87","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.febslet.2009.12.018","article-title":"PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities","volume":"584","author":"Mbikay","year":"2010","journal-title":"FEBS Lett"},{"key":"10.1016\/j.ajpath.2021.04.016_bib88","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.bbrc.2009.10.138","article-title":"PCSK9 is expressed in pancreatic delta-cells and does not alter insulin secretion","volume":"390","author":"Langhi","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1016\/j.ajpath.2021.04.016_bib89","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/eurheartj\/ehy357","article-title":"PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor","volume":"40","author":"Da Dalt","year":"2019","journal-title":"Eur Heart J"},{"key":"10.1016\/j.ajpath.2021.04.016_bib90","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/1753-0407.12139","article-title":"Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL\/6 mice CSK9PC57BL\/6","volume":"7","author":"Mbikay","year":"2015","journal-title":"J Diabetes"},{"key":"10.1016\/j.ajpath.2021.04.016_bib91","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.atherosclerosis.2021.03.044","article-title":"Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function","volume":"326","author":"Ramin-Mangata","year":"2021","journal-title":"Atherosclerosis"},{"key":"10.1016\/j.ajpath.2021.04.016_bib92","doi-asserted-by":"crossref","first-page":"158968","DOI":"10.1016\/j.bbalip.2021.158968","article-title":"Substantial PCSK9 inactivation in \u03b2-cells does not modify glucose homeostasis or insulin secretion in mice","volume":"866","author":"Peyot","year":"2021","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"10.1016\/j.ajpath.2021.04.016_bib93","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3390\/ijms20020245","article-title":"PCSK9 is expressed in human visceral adipose tissue and regulated by insulin and cardiac natriuretic peptides","volume":"20","author":"Bordicchia","year":"2019","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib94","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1177\/2047487317724342","article-title":"PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans","volume":"24","author":"Baragetti","year":"2017","journal-title":"Eur J Prev Cardiol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib95","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":"10.1016\/j.ajpath.2021.04.016_bib96","doi-asserted-by":"crossref","first-page":"e14721","DOI":"10.14814\/phy2.14721","article-title":"Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome","volume":"9","author":"Cyr","year":"2021","journal-title":"Physiol Rep"},{"key":"10.1016\/j.ajpath.2021.04.016_bib97","doi-asserted-by":"crossref","first-page":"1348913","DOI":"10.1155\/2020\/1348913","article-title":"PCSK9 expression in epicardial adipose tissue: molecular association with local tissue inflammation","volume":"2020","author":"Dozio","year":"2020","journal-title":"Mediators Inflamm"},{"key":"10.1016\/j.ajpath.2021.04.016_bib98","doi-asserted-by":"crossref","first-page":"e007614","DOI":"10.1161\/CIRCEP.119.007614","article-title":"Accumulation of pericardial fat is associated with alterations in heart rate variability patterns in hypercholesterolemic pigs","volume":"13","author":"Uceda","year":"2020","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib99","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.numecd.2016.12.005","article-title":"Translating the biology of adipokines in atherosclerosis and cardiovascular diseases: gaps and open questions","volume":"27","author":"Ruscica","year":"2017","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"10.1016\/j.ajpath.2021.04.016_bib100","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1161\/ATVBAHA.117.309630","article-title":"Activation of adiponectin receptor regulates proprotein convertase subtilisin\/kexin type 9 expression and inhibits lesions in ApoE-deficient mice","volume":"37","author":"Sun","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib101","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1016\/j.ajpath.2020.07.016","article-title":"Resistin, and proprotein convertase subtilisin\/kexin type 9: the role of STAT3","volume":"190","author":"Macchi","year":"2020","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib102","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1210\/en.2015-1624","article-title":"Effect of leptin replacement on PCSK9 in ob\/ob mice and female lipodystrophic patients","volume":"157","author":"Levenson","year":"2016","journal-title":"Endocrinology"},{"key":"10.1016\/j.ajpath.2021.04.016_bib103","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1016\/j.jacc.2011.11.064","article-title":"Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin\/kexin type 9","volume":"59","author":"Melone","year":"2012","journal-title":"J Am Coll Cardiol"},{"key":"10.1016\/j.ajpath.2021.04.016_bib104","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s42255-020-0174-0","article-title":"Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities","volume":"2","author":"Huang","year":"2020","journal-title":"Nat Metab"},{"key":"10.1016\/j.ajpath.2021.04.016_bib105","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.1038\/s41467-018-06467-9","article-title":"A Mendelian randomization study of the effects of blood lipids on breast cancer risk","volume":"9","author":"Nowak","year":"2018","journal-title":"Nat Commun"},{"key":"10.1016\/j.ajpath.2021.04.016_bib106","doi-asserted-by":"crossref","first-page":"559","DOI":"10.5114\/aoms.2019.84732","article-title":"Potential anti-tumor effect of a nanoliposomal antiPCSK9 vaccine in mice bearing colorectal cancer","volume":"15","author":"Momtazi-Borojeni","year":"2019","journal-title":"Arch Med Sci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib107","doi-asserted-by":"crossref","first-page":"570","DOI":"10.5114\/aoms.2019.84734","article-title":"Effects of immunization against PCSK9 in an experimental model of breast cancer","volume":"15","author":"Momtazi-Borojeni","year":"2019","journal-title":"Arch Med Sci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib108","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.3892\/etm.2017.4218","article-title":"PCSK9 regulates apoptosis in human lung adenocarcinoma A549 cells via endoplasmic reticulum stress and mitochondrial signaling pathways","volume":"13","author":"Xu","year":"2017","journal-title":"Exp Ther Med"},{"key":"10.1016\/j.ajpath.2021.04.016_bib109","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41586-020-2911-7","article-title":"Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer","volume":"588","author":"Liu","year":"2020","journal-title":"Nature"},{"key":"10.1016\/j.ajpath.2021.04.016_bib110","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.jacbts.2020.05.004","article-title":"Genetic and in\u00a0vitro inhibition of PCSK9 and calcific aortic valve stenosis","volume":"5","author":"Perrot","year":"2020","journal-title":"JACC Basic Transl Sci"},{"key":"10.1016\/j.ajpath.2021.04.016_bib111","doi-asserted-by":"crossref","first-page":"105222","DOI":"10.1016\/j.phrs.2020.105222","article-title":"Unlike estrogens that increase PCSK9 levels post-menopause HSP27 vaccination lowers cholesterol levels and atherogenesis due to divergent effects on PCSK9 and LDLR","volume":"161","author":"Maarouf","year":"2020","journal-title":"Pharmacol Res"},{"key":"10.1016\/j.ajpath.2021.04.016_bib112","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1161\/CIRCULATIONAHA.120.051940","article-title":"PCSK9 (proprotein convertase subtilisin\/kexin 9) goes \u201cDAMP.\u201d","volume":"143","author":"Silverstein","year":"2021","journal-title":"Circulation"}],"container-title":["The American Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002944021002042?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002944021002042?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T11:07:51Z","timestamp":1762081671000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0002944021002042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":112,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["S0002944021002042"],"URL":"https:\/\/doi.org\/10.1016\/j.ajpath.2021.04.016","relation":{},"ISSN":["0002-9440"],"issn-type":[{"value":"0002-9440","type":"print"}],"subject":[],"published":{"date-parts":[[2021,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Proprotein Convertase Subtilisin\/Kexin Type 9","name":"articletitle","label":"Article Title"},{"value":"The American Journal of Pathology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ajpath.2021.04.016","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 American Society for Investigative Pathology. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}