TY - JOUR T1 - SIRT1 mediates the actions of PPARδ on the oxLDL-triggered migration and proliferation of vascular smooth muscle cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.116.104679 SP - mol.116.104679 AU - Jung Seok Hwang AU - Sun Ah Ham AU - Taesik Yoo AU - Won Jin Lee AU - Kyung Shin Paek AU - Chi-Ho Lee AU - Han Geuk Seo Y1 - 2016/01/01 UR - http://molpharm.aspetjournals.org/content/early/2016/08/29/mol.116.104679.abstract N2 - Peroxisome proliferator-activated receptor (PPAR) δ has been implicated in the vascular pathophysiology. However, its functions in the atherogenic changes of the vascular wall are not fully elucidated. GW501516-activated PPARδ significantly inhibited oxidized low-density lipoprotein (oxLDL)-triggered migration and proliferation of vascular smooth muscle cells (VSMCs). These GW501516-mediated effects were significantly reversed by PPARδ-targeting siRNA, indicating that PPARδ is involved in the action of GW501516. Anti-proliferative effect of GW501516 was directly linked to cell cycle arrest at the G0/G1 to S phase transition, which was followed by the down-regulation of cyclin-dependent kinase 4 along with increased levels of p21 and p53. In VSMCs treated with GW501516, the expression of SIRT1 mRNA and protein was time-dependently increased. This GW501516-mediated upregulation of SIRT1 expression was also demonstrated even in the presence of oxLDL. In addition, GW501516-dependent inhibition of oxLDL-triggered migration and proliferation of VSMCs was almost completely abolished in the presence of SIRT1-targeting siRNA. These effects of GW501516 on oxLDL-triggered phenotypic changes of VSMCs were also demonstrated via activation or inhibition of SIRT1 activity by resveratrol or sirtinol, respectively. Finally, gain or loss of SIRT1 function imitated the action of PPARδ on oxLDL-triggered migration and proliferation of VSMCs. Taken together, these observations indicate that PPARδ-dependent upregulation of SIRT1 contributes to the anti-atherogenic activities of PPARδ by suppressing the migration and proliferation of VSMCs linked to vascular diseases such as restenosis and atherosclerosis. ER -