title: The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition.
abstract: Pulmonary fibrosis is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix components. Although the origin of fibroblasts is multifactorial, recent data implicate endothelial-to-mesenchymal transition as an important source of fibroblasts. We report herein that loss of the essential autophagy gene ATG7 in endothelial cells (ECs) leads to impaired autophagic flux accompanied by marked changes in EC architecture, loss of endothelial, and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition. Loss of ATG7 also up-regulates TGFβ signaling and key pro-fibrotic genes in vitro. In vivo, EC-specific ATG7 knock-out mice exhibit a basal reduction in endothelial-specific markers and demonstrate an increased susceptibility to bleomycin-induced pulmonary fibrosis and collagen accumulation. Our findings help define the role of endothelial autophagy as a potential therapeutic target to limit organ fibrosis, a condition for which presently there are no effective available treatments.
authors.affiliation: From the Divisions of Cardiac Surgery, Vascular Surgery, Departments of Surgery and Departments of Surgery and.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Azza
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: Cardiology, Medicine, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
authors.forename: Pratiek N
authors.initials: PN
authors.lastname: Matkar
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Mehroz
authors.initials: M
authors.lastname: Ehsan
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Paul
authors.initials: P
authors.lastname: Sandhu
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mantella
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and.
authors.forename: Nandini
authors.initials: N
authors.lastname: Gupta
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and Medicine, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada, Endocrinology and Metabolism, and.
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.affiliation: Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada.
authors.forename: Matteo
authors.initials: M
authors.lastname: Parotto
authors.affiliation: Departments of Surgery and.
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: Departments of Surgery and Departments of Surgery and Physiology and Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: Vascular Surgery, Departments of Surgery and Departments of Surgery and King Saud University-Li Ka Shing Collaborative Research Program, Riyadh 12372, Kingdom of Saudi Arabia, and.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.affiliation: Center for Molecular Medicine, NHLBI, National Institutes of Health Bethesda, Maryland 20892.
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.affiliation: From the Divisions of Cardiac Surgery, Departments of Surgery and Departments of Surgery and King Saud University-Li Ka Shing Collaborative Research Program, Riyadh 12372, Kingdom of Saudi Arabia, and vermasu@smh.ca.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D000071193:Autophagy-Related Protein 7; D001761:Bleomycin / Q000633:toxicity; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology*; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D001761:Bleomycin; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes
keywords: Autophagy; Autophagy-related Protein 7 (ATG7); Endothelial Cell; Endothelial-to-mesenchymal Transition; Gene Silencing; Pulmonary Fibrosis