PPAR delta modulates oxLDL-induced apoptosis of vascular smooth muscle cells through a TGF-beta/FAK signaling axis

摘要

The peroxisome proliferator-activated receptor delta (PPAR delta) has been implicated in the modulation of vascular homeostasis. However, its roles in the apoptotic cell death of vascular smooth muscle cells (VSMCs) are poorly understood. Here, we demonstrate that PPAR delta modulates oxidized low-density lipoprotein (oxLDL)-induced apoptosis of VSMCs through the transforming growth factor-beta (TGF-delta) and focal adhesion kinase (FAK) signaling pathways. Activation of PPAR delta by GW501516, which is a specific ligand, significantly inhibited oxLDL-induced cell death and generation of reactive oxygen species in VSMCs. These inhibitory effects were significantly reversed in the presence of small interfering (si)RNA against PPAR delta, or by blockade of the TGF-beta or FAK signaling pathways. Furthermore, PPAR delta-mediated recovery of FAK phosphorylation suppressed by oxLDL was reversed by SB431542, a specific ALK5 receptor inhibitor, indicating that a TGF-beta/FAK signaling axis is involved in the action of PPAR delta. Among the protein kinases activated by oxLDL, p38 mitogen-activated protein kinase was suppressed by ligand-activated PPAR delta. In addition, oxLDL-induced expression and translocation of pro-apoptotic or anti-apoptotic factors were markedly affected in the presence of GW501516. Those effects were reversed by PPAR delta siRNA, or inhibitors of TGF-beta or FAK, which also suggests that PPAR delta exerts its anti-apoptotic effect via a TGF-beta/FAK signaling axis. Taken together, these findings indicate that PPAR delta plays an important role in the pathophysiology of disease associated with apoptosis of VSMC, such as atherosclerosis and restanosis. (C) 2015 Elsevier Ltd. All rights reserved.