title: Macrophage autophagy plays a protective role in advanced atherosclerosis.
abstract: In advanced atherosclerosis, macrophage apoptosis coupled with defective phagocytic clearance of the apoptotic cells (efferocytosis) promotes plaque necrosis, which precipitates acute atherothrombotic cardiovascular events. Oxidative and endoplasmic reticulum (ER) stress in macrophages are important causes of advanced lesional macrophage apoptosis. We now show that proapoptotic oxidative/ER stress inducers trigger another stress reaction in macrophages, autophagy. Inhibition of autophagy by silencing ATG5 or other autophagy mediators enhances apoptosis and NADPH oxidase-mediated oxidative stress while at the same time rendering the apoptotic cells less well recognized by efferocytes. Most importantly, macrophage ATG5 deficiency in fat-fed Ldlr(-/-) mice increases apoptosis and oxidative stress in advanced lesional macrophages, promotes plaque necrosis, and worsens lesional efferocytosis. These findings reveal a protective process in oxidatively stressed macrophages relevant to plaque necrosis, suggesting a mechanism-based strategy to therapeutically suppress atherosclerosis progression and its clinical sequelae.
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Xianghai
authors.initials: X
authors.lastname: Liao
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Manikandan
authors.initials: M
authors.lastname: Subramanian
authors.forename: Kristy
authors.initials: K
authors.lastname: Brown
authors.forename: J Scott
authors.initials: JS
authors.lastname: Pattison
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000473:pathology*; D001343:Autophagy; D019610:Cytoprotection; D008264:Macrophages / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology
chemical_list: D019255:NADPH Oxidases