Autophagy links inflammasomes to atherosclerotic progression

Babak Razani, Chu Feng, Trey Coleman, Roy Emanuel, Haitao Wen, Seungmin Hwang, Jenny P. Ting, Herbert W. Virgin, Michael B. Kastan, Clay F. Semenkovich

Research output: Contribution to journalArticle

295 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)534-544
Number of pages11
JournalCell Metabolism
Volume15
Issue number4
DOIs
StatePublished - Apr 4 2012
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Razani, B., Feng, C., Coleman, T., Emanuel, R., Wen, H., Hwang, S., Ting, J. P., Virgin, H. W., Kastan, M. B., & Semenkovich, C. F. (2012). Autophagy links inflammasomes to atherosclerotic progression. Cell Metabolism, 15(4), 534-544. https://doi.org/10.1016/j.cmet.2012.02.011