{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:27:47Z","timestamp":1791311267045,"version":"4.3.1"},"reference-count":48,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,3,7]],"date-time":"2017-03-07T00:00:00Z","timestamp":1488844800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","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":[[2017,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recent studies have shown that in addition to being major constituents of the atheromatous core, solid cholesterol crystals (<jats:styled-content style=\"fixed-case\">CCs<\/jats:styled-content>) promote atherosclerotic lesion development and rupture by causing mechanical damage and exerting cytotoxic and pro\u2010inflammatory effects. These findings suggest that targeting <jats:styled-content style=\"fixed-case\">CCs<\/jats:styled-content> might represent a therapeutic strategy for plaque stabilization. However, little is known about how cholesterol crystallization is initiated in human atherothrombotic disease. Here, we investigated these mechanisms. We performed a thorough immunohistological analysis of non\u2010embedded, minimally processed human aortic tissues, combining polarized light and fluorescence microscopy. We found that <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content> formation was initiated during the fatty streak to fibroatheroma transition in tight association with the death of intralesional smooth muscle cells (<jats:styled-content style=\"fixed-case\">SMCs<\/jats:styled-content>). Cholesterol\u2010loaded human <jats:styled-content style=\"fixed-case\">SMCs<\/jats:styled-content> were capable of producing <jats:styled-content style=\"fixed-case\">CCs<\/jats:styled-content> <jats:italic>in vitro<\/jats:italic>, a process that was enhanced by type I collagen and by inhibition of autophagy and cholesterol esterification. The fibrous transition, which was characterized by increased type I collagen expression, was associated with changes in the expression of autophagy and cholesterol flux\u2010related genes, including a decrease in the autophagic adapter p62 and an increase in the cholesterol intracellular transporter Niemann\u2013Pick <jats:styled-content style=\"fixed-case\">C1<\/jats:styled-content>. Collagen was identified as a potent inducer of these changes in <jats:styled-content style=\"fixed-case\">SMCs<\/jats:styled-content>. Collagen\u2010induced changes in cholesterol metabolism and autophagy flux in smooth muscle foam cells at the fibrolipid transition likely contribute to initiate cholesterol crystallization in human atherosclerosis. Also, our data are in support of a protective role of autophagy against <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content> formation. Copyright \u00a9 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4873","type":"journal-article","created":{"date-parts":[[2016,12,31]],"date-time":"2016-12-31T03:42:50Z","timestamp":1483155770000},"page":"671-682","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Cholesterol crystallization in human atherosclerosis is triggered in smooth muscle cells during the transition from fatty streak to fibroatheroma"],"prefix":"10.1002","volume":"241","author":[{"given":"Beno\u00eet","family":"Ho\u2010Tin\u2010No\u00e9","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Vo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Bayles","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Ferri\u00e8re","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayette","family":"Ladjal","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sondes","family":"Toumi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Deschildre","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Ollivier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Baptiste","family":"Michel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9 Laboratory for Vascular Translational Science  INSERM Unit 1148 Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.676890"},{"key":"e_1_2_7_3_1","first-page":"1","article-title":"Ueber experimentelle Choleserinsteatose und ihre Bedeutung fur die Entstehung einiger pathologischer Prozesse","volume":"24","author":"Anitschkow N","year":"1913","journal-title":"Zentralbl Allg Pathol Pathol Anat"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108450"},{"key":"e_1_2_7_5_1","first-page":"193","article-title":"Human aortic fibrolipid lesions. Progenitor lesions for fibrous plaques, exhibiting early formation of the cholesterol\u2010rich core","volume":"120","author":"Bocan TM","year":"1985","journal-title":"Am J Pathol"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106365"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(63)90580-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.15.9.1512"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2010.03.003"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/sca.4950280101"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2008.12.019"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08938"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(94)90657-2"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv653"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9150(78)90047-3"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)40131-2"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)37177-7"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2008.06.027"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.235390"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH05-07-0505"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1253\/jcj.37.269"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)40608-X"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.69.12.3795"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.08.065"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.18.5.738"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011765"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201041316"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1177\/002215540305100608"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/183873a0"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(98)00044-6"},{"key":"e_1_2_7_31_1","first-page":"413","article-title":"Ultrastructure of the human aortic fibrolipid lesion. Formation of the atherosclerotic lipid\u2010rich core","volume":"123","author":"Bocan TM","year":"1986","journal-title":"Am J Pathol"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.005015"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.106.134080"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119813"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2015.05.011"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(97)00136-6"},{"key":"e_1_2_7_37_1","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S0003-4967(24)43164-6","article-title":"CD68 is not a macrophage\u2010specific antigen","volume":"64","author":"Beranek JT","year":"2005","journal-title":"Ann Rheum Dis"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304029"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3866"},{"key":"e_1_2_7_40_1","first-page":"49","article-title":"Cholesterol crystals, smooth muscle cells and new data on the genesis of atherosclerosis","volume":"48","author":"Kiyak JH","year":"1997","journal-title":"Pol J Pathol"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.03.023"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.02.011"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1096485"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2011.07.022"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1035"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.18.12.1964"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080734"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2012.482"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1679\/aohc1950.41.267"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4873","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4873","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:16:31Z","timestamp":1760955391000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,7]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,4]]}},"alternative-id":["10.1002\/path.4873"],"URL":"https:\/\/doi.org\/10.1002\/path.4873","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,7]]},"assertion":[{"value":"2016-08-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-03-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}