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Recent studies demonstrated that the ligand-activated transcription factor peroxisome proliferator-activated receptor α (PPARα) acts in association with histone deacetylase sirtuin 1 (SIRT1) in the regulation of metabolism and inflammation involved in cardiovascular diseases.PPARα activation also participates inthe modulation of cell apoptosis.Our previous study found that SIRT1 inhibits the apoptosis of vascular adventitial fibroblasts (VAFs).However,whether the role of PPARα in apoptosis of VAFs is mediated by SIRT1 remains unknown.In this study, we aimed to determine the effect of PPARα agonist fenofibrate on cell apoptosis and SIRT1 expression and related mechanisms in ApoE-/ mice and VAFs in vitro.We found that fenofibrate inhibited cell apoptosis in vascular adventitia and up-regulated SIRT1 expression in aorta of ApoE-/-mice.Moreover, SIRT1 activator resveratrol (RSV) further enhanced these effects of fenofibrate.In vitro study showed that activation of PPARα by fenofibrate inhibited TNF-α-induced cell apoptosis and cell cycle arrest in VAFs.Meanwhile, fenofibrate up-regulated SIRT1 expression and inhibited SIRT1 translocation from nucleus to cytoplasm in VAFs stimulated with TNF-α.Moreover, the effects of fenofibrate on cell apoptosis and SIRT1 expression in VAFs were reversed by PPARα antagonist GW6471.Importantly, treatment of VAFs with SIRT 1 siRNA or pcDNA3.1 (+)-SIRT 1 showed that the inhibitory effect of fenofibrate on cell apoptosis in VAFs through SIRT1.On the other hand, knockdown of FoxOldecreased cell apoptosis of VAFs compared with fenofibrate group.Overexpression of FoxO 1 increased cell apoptosis of VAFs compared with fenofibrate group.Further study found that fenofibrate decreased the expression of acetylated-FoxO 1 in TNF-α-stimulated VAFs, which was abolished by SIRT1 knockdown.Takentogether, these findings indicate that activation of PPARαt by fenofibrate inhibits cell apoptosis in VAFs partly through the SIRT 1-mediated deacetylation of FoxO1.