Activation of AMPK/Sirt3 pathway by phloretin reduces mitochondrial ROS in vascular endothelium through increasing the activity of MnSOD via deacetylation

As a dihydrochalcone, phloretin was reported to effectively attenuate palmitic acid (PA)-induced oxidative stress in endothelial cells. In the present study, we further investigated the antioxidant capacity of phloretin via restoring the activity of MnSOD through deacetylation in vitro and in vivo. The results revealed that phloretin (50 μM) treatment significantly increased the activity of MnSOD in HUVECs and mice aorta, and then obviously reduced the accumulation of mitochondrial ROS production. Immunoprecipitation assay and Western blot analysis indicated that phloretin could decrease the lysine acetylation of MnSOD and restore its activity by promoting the expression of Sirt3 through increasing the phosphorylation of AMPKThr172. These findings provide a novel profile to explain the antioxidant activity of phloretin through reducing the acetylation level of MnSOD via an AMPK/Sirt3 signaling pathway.