Sirtuin 1 Mediates the Actions of Peroxisome Proliferator-Activated Receptor delta on the Oxidized Low-Density Lipoprotein-Triggered Migration and Proliferation of Vascular Smooth Muscle Cells

摘要

Peroxisome proliferator-activated receptor delta (PPAR delta) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPAR delta activated by GW501516 (2-[2-methyl-4-[[4methyl-2-[4-(trifluoromethyl) phenyl]-1,3-thiazol-5-yl] methylsulfanyl]phenoxy] acetic acid) significantly inhibited the migration and proliferation of vascular smooth muscle cells (VSMCs) triggered by oxidized low-density lipoprotein (oxLDL). These GW501516mediated effects were significantly reversed by PPAR delta-targeting small-interfering RNA (siRNA), indicating that PPAR delta is involved in the action ofGW501516. The antiproliferative effect ofGW501516 was directly linked to cell cycle arrest at the G(0)/G(1) to S phase transition, which was followed by the down-regulation of cyclindependent kinase 4 along with increased levels of p21 and p53. In VSMCs treated with GW501516, the expression of sirtuin 1 (SIRT1) mRNA and protein was time-dependently increased. ThisGW501516-mediated up-regulation 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 PPAR delta on oxLDLtriggered migration and proliferation of VSMCs. Taken together, these observations indicate that PPAR delta-dependent up-regulation of SIRT1 contributes to the antiatherogenic activities of PPAR delta by suppressing the migration and proliferation of VSMCs linked to vascular diseases such as restenosis and atherosclerosis.