[PDF][PDF] Autophagy links inflammasomes to atherosclerotic progression

B Razani, C Feng, T Coleman, R Emanuel, H Wen… - Cell metabolism, 2012 - cell.com
B Razani, C Feng, T Coleman, R Emanuel, H Wen, S Hwang, JP Ting, HW Virgin
Cell metabolism, 2012cell.com
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 …
Summary
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.
cell.com