Activation of PPAR alpha by fenofibrate inhibits apoptosis in vascular adventitial fibroblasts partly through SIRT1-mediated deacetylation of FoxO1

作者：Wang, Wei-rong; Liu, En-qi; Zhang, Ji-ye; Li, Yan-xiang; Yang, Xiao-feng; He, Yan-hao; Zhang, Wei; Jing, Ting; Lin, Rong^*

来源：Experimental Cell Research, 2015, 338(1): 54-63.

DOI：10.1016/j.yexcr.2015.07.027

• PPAR alpha
• SIRT1
• FoxO1
• Apoptosis
• Vascular adventitial fibroblasts

Recent studies demonstrated that the ligand-activated transcription factor peroxisome proliferator-activated receptor alpha (PPAR alpha) acts in association with histone deacetylase sirtuin 1 (SIRT1) in the regulation of metabolism and inflammation involved in cardiovascular diseases. PPAR alpha 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 PPAR alpha in apoptosis of VAFs is mediated by SIRT1 remains unknown. In this study, we aimed to determine the effect of PPAR alpha 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 PPAR alpha by fenofibrate inhibited TNF-alpha-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-alpha. Moreover, the effects of fenofibrate on cell apoptosis and SIRT1 expression in VAFs were reversed by PPAR alpha 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-alpha-stimulated VAFs, which was abolished by SIRT1 knockdown. Taken together, these findings indicate that activation of PPAR alpha by fenofibrate inhibits cell apoptosis in VAFs partly through the SIRT1-mediated deacetylation of FoxO1.

• 出版日期2015-10-15
• 单位西安交通大学