PPARδ modulates oxLDL-induced apoptosis of vascular smooth muscle cells through a TGF-β/FAK signaling axis. (May 2015)

• Record Type: Journal Article
• Authors: Hwang, Jung Seok; Eun, So Young; Ham, Sun Ah; Yoo, Taesik; Lee, Won Jin; Paek, Kyung Shin; Do, Jeong Tae; Lim, Dae-Seog; Seo, Han Geuk
• Is Part Of: International journal of biochemistry & cell biology. Volume 62(2015:May)
• Page Start: 54
• Page End: 61
• Publication Date: 2015-05
• Subjects: ERK extracellular signal-regulated kinases -- FAK focal adhesion kinase -- JNK c-Jun N-terminal kinase -- MAPKs mitogen-activated protein kinases -- NAC N-acetyl-l-cysteine -- oxLDL oxidized low-density lipoprotein -- PI3K phosphatidylinositide 3-kinases -- PPAR peroxisome proliferator-activated receptor -- ROS reactive oxygen species -- TGF-β transforming growth factor-β -- VSMCs vascular smooth muscle cells; Apoptosis -- Focal adhesion kinase -- Oxidized low-density lipoprotein -- Peroxisome proliferator-activated receptor δ -- Transforming growth factor-β; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2015.02.014
• Languages: English
• ISSNs: 1357-2725

Abstract

Graphical abstract: Highlights: oxLDL induces the generation of ROS and apoptotic cell death in VSMCs. oxLDL-provoked ROS generation and apoptosis are suppressed by PPARδ. TGF-β/FAK signal axis contributes to PPARδ-mediated anti-apoptotic actions in VSMCs. PPARδ plays a key role in the disease associated with apoptosis of VSMCs. Abstract: The peroxisome proliferator-activated receptor delta (PPARδ) 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 PPARδ modulates oxidized low-density lipoprotein (oxLDL)-induced apoptosis of VSMCs through the transforming growth factor-β (TGF-β) and focal adhesion kinase (FAK) signaling pathways. Activation of PPARδ 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 PPARδ, or by blockade of the TGF-β or FAK signaling pathways. Furthermore, PPARδ-mediated recovery of FAK phosphorylation suppressed by oxLDL was reversed by SB431542, a specific ALK5 receptor inhibitor, indicating that a TGF-β/FAK signaling axis is involved in the action of PPARδ. Among the protein kinases activated by oxLDL, p38 mitogen-activated protein kinase was suppressed by ligand-activated PPARδ. 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 PPARδ siRNA, or inhibitors of TGF-β or FAK, which also suggests that PPARδ exerts its anti-apoptotic effect via a TGF-β/FAK signaling axis. Taken together, these findings indicate that PPARδ plays an important role in the pathophysiology of disease associated with apoptosis of VSMC, such as atherosclerosis and restanosis.