Epigenetic regulation of NKG2D ligands is involved in exacerbated atherosclerosis development in Sirt6 heterozygous mice

What is it about?

Sirt6 is a member of the class III histone deacetylase family which is associated with aging and longevity. Sirt6 deficient mice show an aging-like phenotype, while male transgenic mice of Sirt6 show increased longevity. Sirt6 acts as a tumor suppressor and deficiency of Sirt6 leads to cardiac hypertrophy and heart failure. Whether Sirt6 is involved in atherosclerosis development, the major cause of cardiovascular diseases, is unknown. We found that the expression of Sirt6 is lower in human atherosclerotic plaques than that in controls. When Sirt6+/−ApoE−/− and ApoE−/− mice are fed with high fat diet for 16 weeks, Sirt6+/−ApoE−/− mice show increased plaque fromation and exhibit feature of plaque instability. Furthermore, Sirt6 downregulation increases expression of NKG2D ligands, which leads to increased cytokine expression. Blocking NKG2D ligand almost completely blocks this effect. Mechanistically, Sirt6 binds to promoters of NKG2D ligand genes and regulates the H3K9 and H3K56 acetylation levels.

Featured Image

Why is it important?

Our study demonstrates that heterozygous Sirt6 mice have more severe atherosclerosis and exhibit feature of less stable atherosclerotic plaques, suggesting the protective roles of Sirt6 in atherosclerosis. Sirt6 regulates H3K9 and H3K56 acetylation levels at the promoters of NKG2D ligands. The protective role of Sirt6 makes Sirt6 a potential target in preventing atherosclerosis.

Perspectives