title: Activation of PPAR alpha by fenofibrate inhibits apoptosis in vascular adventitial fibroblasts partly through SIRT1-mediated deacetylation of FoxO1.
abstract: Recent studies demonstrated that the ligand-activated transcription factor peroxisome proliferator-activated receptorα (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 in the 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 SIRT1 siRNA or pcDNA3.1(+)-SIRT1 showed that the inhibitory effect of fenofibrate on cell apoptosis in VAFs through SIRT1. On the other hand, knockdown of FoxO1 decreased cell apoptosis of VAFs compared with fenofibrate group. Overexpression of FoxO1 increased cell apoptosis of VAFs compared with fenofibrate group. Further study found that fenofibrate decreased the expression of acetylated-FoxO1 in TNF-α-stimulated VAFs, which was abolished by SIRT1 knockdown. Taken together, these findings indicate that activation of PPARα by fenofibrate inhibits cell apoptosis in VAFs partly through the SIRT1-mediated deacetylation of FoxO1.
authors.affiliation: Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, Shaanxi 710061, China; Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Wei-Rong
authors.initials: WR
authors.lastname: Wang
authors.affiliation: Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, Shaanxi 710061, China; Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: En-Qi
authors.initials: EQ
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Yan-Hao
authors.initials: YH
authors.lastname: He
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Jing
authors.affiliation: Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China. Electronic address: linrong@mail.xjtu.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
mesh_terms: D000107:Acetylation; D063194:Adventitia / Q000166:cytology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001808:Blood Vessels / Q000166:cytology; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D011345:Fenofibrate
keywords: Apoptosis; FoxO1; PPARα; SIRT1; Vascular adventitial fibroblasts