{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:08:57Z","timestamp":1790723337625,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,11,13]],"date-time":"2015-11-13T00:00:00Z","timestamp":1447372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01\u2010HL106845"],"award-info":[{"award-number":["R01\u2010HL106845"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Proprotein convertase subtilisin\/kexin type 9 (<jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content>) promotes atherosclerosis by increasing low\u2010density lipoprotein (<jats:styled-content style=\"fixed-case\">LDL<\/jats:styled-content>) cholesterol levels through degradation of hepatic <jats:styled-content style=\"fixed-case\">LDL<\/jats:styled-content> receptor (<jats:styled-content style=\"fixed-case\">LDLR<\/jats:styled-content>). Studies have described the systemic effects of <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> on atherosclerosis, but whether <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> has local and direct effects on the plaque is unknown. To study the local effect of human <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">hPCSK9<\/jats:styled-content>) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing h<jats:italic>PCSK9<\/jats:italic> exclusively from macrophages, using marrow from h<jats:italic>PCSK9<\/jats:italic> transgenic (h<jats:italic>PCSK9<\/jats:italic>tg) mice transplanted into apoE<jats:sup>\u2212\/\u2212<\/jats:sup> and LDLR<jats:sup>\u2212\/\u2212<\/jats:sup> mice, which were then placed on a high\u2010fat diet (HFD) for 8 weeks. We further characterized the effect of h<jats:italic>PCSK9<\/jats:italic> expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) <jats:italic>in vitro<\/jats:italic>. We found that MPMs from transgenic mice express both murine (m) <jats:italic>Pcsk9<\/jats:italic> and h<jats:italic>PCSK9<\/jats:italic> and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with h<jats:italic>PCSK9<\/jats:italic>tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow\u2010derived PCSK9 progressively accumulated in lesions of apoE<jats:sup>\u2212\/\u2212<\/jats:sup> recipient mice, while increasing the infiltration of Ly6C<jats:sup>hi<\/jats:sup> inflammatory monocytes by 32% compared with controls. Expression of h<jats:italic>PCSK9<\/jats:italic> also increased CD11b\u2010 and Ly6C<jats:sup>hi<\/jats:sup>\u2010positive cell numbers in spleens of apoE<jats:sup>\u2212\/\u2212<\/jats:sup> mice. <jats:italic>In vitro<\/jats:italic>, expression of h<jats:italic>PCSK9<\/jats:italic> in LPS\u2010stimulated macrophages increased mRNA levels of the pro\u2010inflammatory markers <jats:italic>Tnf<\/jats:italic> and <jats:italic>Il1b<\/jats:italic> (40% and 45%, respectively) and suppressed those of the anti\u2010inflammatory markers <jats:italic>Il10<\/jats:italic> and <jats:italic>Arg1<\/jats:italic> (30% and 44%, respectively). All <jats:italic>PCSK9<\/jats:italic> effects were LDLR\u2010dependent, as PCSK9 protein was not detected in lesions of LDLR<jats:sup>\u2212\/\u2212<\/jats:sup> recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR\u2010dependent but cholesterol\u2010independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction. Copyright \u00a9 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4630","type":"journal-article","created":{"date-parts":[[2015,9,3]],"date-time":"2015-09-03T06:56:25Z","timestamp":1441263385000},"page":"52-62","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":173,"title":["Local effects of human <scp>PCSK9<\/scp> on the atherosclerotic lesion"],"prefix":"10.1002","volume":"238","author":[{"given":"Ilaria","family":"Giunzioni","sequence":"first","affiliation":[{"name":"Knight Cardiovascular Institute, Center for Preventive Cardiology Oregon Health and Science University  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagai","family":"Tavori","sequence":"additional","affiliation":[{"name":"Knight Cardiovascular Institute, Center for Preventive Cardiology Oregon Health and Science University  Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Covarrubias","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology Vanderbilt University Medical Center  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy S","family":"Major","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology Vanderbilt University Medical Center  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Ding","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Department of Medicine Vanderbilt University Medical Center  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youmin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Department of Medicine Vanderbilt University Medical Center  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel M","family":"DeVay","sequence":"additional","affiliation":[{"name":"Rinat\u2010Pfizer Inc.  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