title: Intact endothelial autophagy is required to maintain vascular lipid homeostasis.
abstract: The physiological role of autophagic flux within the vascular endothelial layer remains poorly understood. Here, we show that in primary endothelial cells, oxidized and native LDL stimulates autophagosome formation. Moreover, by both confocal and electron microscopy, excess native or modified LDL appears to be engulfed within autophagic structures. Transient knockdown of the essential autophagy gene ATG7 resulted in higher levels of intracellular (125) I-LDL and oxidized LDL (OxLDL) accumulation, suggesting that in endothelial cells, autophagy may represent an important mechanism to regulate excess, exogenous lipids. The physiological importance of these observations was assessed using mice containing a conditional deletion of ATG7 within the endothelium. Following acute intravenous infusion of fluorescently labeled OxLDL, mice lacking endothelial expression of ATG7 demonstrated prolonged retention of OxLDL within the retinal pigment epithelium (RPE) and choroidal endothelium of the eye. In a chronic model of lipid excess, we analyzed atherosclerotic burden in ApoE(-/-) mice with or without endothelial autophagic flux. The absence of endothelial autophagy markedly increased atherosclerotic burden. Thus, in both an acute and chronic in vivo model, endothelial autophagy appears critically important in limiting lipid accumulation within the vessel wall. As such, strategies that stimulate autophagy, or prevent the age-dependent decline in autophagic flux, might be particularly beneficial in treating atherosclerotic vascular disease.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Torisu
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.|Division of Vascular Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Torisu
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Azza
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: Division of Vascular Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.affiliation: Department of Ophthalmology and Vision Sciences, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Pankova
authors.affiliation: Department of Ophthalmology and Vision Sciences, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Shelley R
authors.initials: SR
authors.lastname: Boyd
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D055213:Retinal Pigment Epithelium / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein
keywords: atherosclerosis; autophagy; lipids; mouse