Autophagy links inflammasomes to atherosclerotic progression.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Razani, B; Feng, C; Coleman, T; Emanuel, R; Wen, H; Hwang, S; Ting, JP; Virgin, HW; Kastan, MB; Semenkovich, CF

Published Date

  • April 4, 2012

Published In

Volume / Issue

  • 15 / 4

Start / End Page

  • 534 - 544

PubMed ID

  • 22440612

Pubmed Central ID

  • 22440612

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2012.02.011

Language

  • eng

Conference Location

  • United States