title: Endothelial-specific deletion of autophagy-related 7 (ATG7) attenuates arterial thrombosis in mice.
abstract: Thrombosis persists as a leading cause of morbidity and mortality. Given that endothelial cells (ECs) play a central role in regulating thrombosis, understanding the molecular endothelial cues that regulate susceptibility or resistance to thrombosis have important translational implications. Accordingly, we evaluated the role of endothelial autophagy in the development of thrombosis.
  
  
  
  We generated mice in which the essential autophagy-related 7 (ATG7) gene was conditionally deleted from ECs (EC-ATG7-/-mice). Three in vivo models of thrombosis were used, and mechanistic studies were conducted with cultured human umbilical vein endothelial cells (HUVECs).
  
  
  
  We silenced ATG7 in HUVECs and observed >60% decreases in tumor necrosis factor (TNF)-α-induced tissue factor (TF) transcript levels, protein expression, and activity. TF mRNA levels in the carotid arteries of EC-ATG7-/-mice subjected to the prothrombotic stimulus FeCl3were lower than those in the similarly treated wild-type (WT) littermate group. Compared with WT mice, EC-ATG7-/-mice exhibited prolonged time to carotid (2-fold greater) and mesenteric (1.3-fold greater) artery occlusion following FeCl3injury. The thrombi generated in laser-injured cremasteric arterioles were smaller in EC-ATG7-/-mice compared with WT mice, and took 2.3-fold longer to appear.
  
  
  
  Taken together, these results provide definitive evidence that loss of endothelial ATG7 attenuates thrombosis and reduces the expression of TF. Our findings demonstrate that endothelial ATG7, and thus autophagy, is a critical and previously unrecognized target for modulating the susceptibility to thrombosis.
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yau
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: singhk@smh.ca.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Xi
authors.initials: X
authors.lastname: Lei
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Azza
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.affiliation: Department of Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, King Saud University and the King Saud University-Li Ka Shing Collaborative Research Program, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bobby
authors.initials: B
authors.lastname: Yanagawa
authors.affiliation: Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address: vermasu@smh.ca.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D000071193:Autophagy-Related Protein 7; D002339:Carotid Arteries / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008638:Mesenteric Arteries / Q000378:metabolism; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000071193:Autophagy-Related Protein 7
keywords: ATG7; autophagy; thrombosis