Protective Effect of Hydroxytyrosol Acetate against Inflammation of Vascular Endothelial Cells partly through SIRT6-mediated PKM2 Signaling Pathway
Hydroxytyrosol acetate (HT-AC), a polyphenolic compound in olive oil, exerts an anti-inflammatory effect in murine collagen-induced arthritis. However, the effect of HT-AC on inflammatory response in cardiovascular diseases remains unclear. Thus, in this study, we aimed to investigate the effect of HT-AC on inflammation response of vascular endothelial cells and related molecular mechanism. Our results showed that HT-AC inhibited inflammatory response in hypercholesterolemic mice and tumor necrosis factor-alpha (TNF-α)-stimulated HUVECs. Meanwhile, HT-AC also up-regulated SIRT6 expression in hypercholesterolemic mice and HUVECs. To further investigate whether SIRT6 is involved in the regulation of HT-AC on endothelial inflammatory response, endothelium-specific SIRT6 knockout (SIRT6endo-/-) mice were used. Our study found that SIRT6endo-/- abolished the inhibition of HT-AC on inflammatory response of thoracic aorta in hypercholesterolemic mice. In vitro study also showed that knockdown of SIRT6 reduced the inhibition of HT-AC on inflammatory response, whereas overexpression of SIRT6 augmented the inhibition of HT-AC on inflammatory response in HUVECs. Further study demonstrated that HT-AC exerts its anti-inflammatory effect partly via the SIRT6-mediated PKM2 signaling pathway. In addition, HT-AC inhibited TNF-α-induced inflammatory response through TNF-α receptor type 1 (TNFR1). These findings indicate that HT-AC regulates the vascular endothelial inflammatory response partly through TNFR1/SIRT6/PKM2-mediated signaling pathway.