title: Cholesterol crystallization in human atherosclerosis is triggered in smooth muscle cells during the transition from fatty streak to fibroatheroma.
abstract: Recent studies have shown that in addition to being major constituents of the atheromatous core, solid cholesterol crystals (CCs) promote atherosclerotic lesion development and rupture by causing mechanical damage and exerting cytotoxic and pro-inflammatory effects. These findings suggest that targeting CCs 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-embedded, minimally processed human aortic tissues, combining polarized light and fluorescence microscopy. We found that CC formation was initiated during the fatty streak to fibroatheroma transition in tight association with the death of intralesional smooth muscle cells (SMCs). Cholesterol-loaded human SMCs were capable of producing CCs in vitro, 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-related genes, including a decrease in the autophagic adapter p62 and an increase in the cholesterol intracellular transporter Niemann-Pick C1. Collagen was identified as a potent inducer of these changes in SMCs. Collagen-induced 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 CC formation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Ho-Tin-Noé
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vo
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Bayles
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ferrière
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Hayette
authors.initials: H
authors.lastname: Ladjal
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Sondes
authors.initials: S
authors.lastname: Toumi
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Deschildre
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Ollivier
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, INSERM Unit, 1148, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
mesh_terms: D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D003460:Crystallization; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology
chemical_list: D024042:Collagen Type I; D002784:Cholesterol
keywords: atheromatous disease; atherosclerosis; autophagy; cholesterol; cholesterol crystals; fatty streak; fibrolipidic lesion; smooth muscle cells; type I collagen