PPARδ modulates oxLDL-induced apoptosis of vascular smooth muscle cells through a TGF-β/FAK signaling axis.
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.
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Jung Seok
JS
Hwang
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
So Young
SY
Eun
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Sun Ah
SA
Ham
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Taesik
T
Yoo
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Won Jin
WJ
Lee
Department of Nursing, Semyung University, 65 Semyung-ro, Jecheon, Chungbuk 390-711, Republic of Korea.
Kyung Shin
KS
Paek
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea.
Jeong Tae
JT
Do
Department of Applied Bioscience, CHA University, 355 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi-do 463-400, Republic of Korea.
Dae-Seog
DS
Lim
Department of Animal Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-Gu, Seoul 143-701, Republic of Korea. Electronic address: hgseo@konkuk.ac.kr.
Han Geuk
HG
Seo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism
C425931:GW 501516; D008077:Lipoproteins, LDL; D047494:PPAR delta; D034741:RNA, Small Interfering; D013844:Thiazoles; D016212:Transforming Growth Factor beta; C099252:oxidized low density lipoprotein; D051416:Focal Adhesion Protein-Tyrosine Kinases
Apoptosis; Focal adhesion kinase; Oxidized low-density lipoprotein; Peroxisome proliferator-activated receptor δ; Transforming growth factor-β