ABSTRACT Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a protective effect in AS, but whether it regulates macrophage polarisation in AS remains uncertain. We aimed to characterise the mechanistic role of SIRT6 in atherosclerosis development mediated by macrophage polarisation. ApoE −/− mice were fed a Western diet to construct the AS mouse model, and LPS treatment was performed on RAW264.7 cells to induce an inflammation cell model. Quantitative real‐time PCR was performed to measure the expression of SIRT6 and M1/M2 macrophage polarisation markers. Plaque size was evaluated by Oil red O staining. M1/M2 macrophage polarisation was evaluated by immunofluorescence staining. The underlying mechanism was determined by Western blot, immunoprecipitation (IP), and co‐IP. Results suggested that SIRT6 was downregulated in the AS mouse model and LPS‐induced macrophages. SIRT6 overexpression decreased plaque size and blood lipid levels in the AS mouse model and inhibited macrophages polarisation to the M1‐like phenotype both in vivo and in vitro. Mechanically, SIRT6 overexpression downregulated the protein level of TLR4 by decreasing acetylation on TLR4. Moreover, TLR4 overexpression restored M1 macrophage polarisation in LPS‐induced macrophages inhibited by SIRT6 overexpression. In conclusion, we demonstrated that SIRT6 attenuated AS by suppressing M1 macrophage polarisation through downregulating TLR4 by deacetylation. These results may provide a potential therapeutic target for targeted macrophage polarisation therapy for AS.
Huang et al. (Sun,) studied this question.