title: Autophagy links inflammasomes to atherosclerotic progression.
abstract: We investigated the role of autophagy in atherosclerosis. During plaque formation in mice, autophagic markers colocalized predominantly with macrophages (mφ). Atherosclerotic aortas had elevated levels of p62, suggesting that dysfunctional autophagy is characteristic of plaques. To determine whether autophagy directly influences atherogenesis, we characterized Beclin-1 heterozygous-null and mφ-specific ATG5-null (ATG5-mφKO) mice, commonly used models of autophagy haploinsufficiency and deficiency, respectively. Haploinsufficent Beclin-1 mice had no atherosclerotic phenotype, but ATG5-mφKO mice had increased plaques, suggesting an essential role for basal levels of autophagy in atheroprotection. Defective autophagy is associated with proatherogenic inflammasome activation. Classic inflammasome markers were robustly induced in ATG5-null mφ, especially when coincubated with cholesterol crystals. Moreover, cholesterol crystals appear to be increased in ATG5-mφKO plaques, suggesting a potentially vicious cycle of crystal formation and inflammasome activation in autophagy-deficient plaques. These results show that autophagy becomes dysfunctional in atherosclerosis and its deficiency promotes atherosclerosis in part through inflammasome hyperactivation.
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis MO 63110, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.forename: Chu
authors.initials: C
authors.lastname: Feng
authors.forename: Trey
authors.initials: T
authors.lastname: Coleman
authors.forename: Roy
authors.initials: R
authors.lastname: Emanuel
authors.forename: Haitao
authors.initials: H
authors.lastname: Wen
authors.forename: Seungmin
authors.initials: S
authors.lastname: Hwang
authors.forename: Jenny P
authors.initials: JP
authors.lastname: Ting
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002784:Cholesterol / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D057895:Haploinsufficiency / Q000187:drug effects; D006579:Heterozygote; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D058847:Inflammasomes; D002784:Cholesterol