PPARgamma activation abolishes LDL-induced proliferation of human aortic smooth muscle cells via SOD-mediated down-regulation of superoxide.
Native LDL would be a mitogenic and chemotactic stimulus of VSMC proliferation and differentiation in the atherosclerotic lesion where endothelial disruption occurred. In previous studies, our group investigated the molecular mechanisms by which LDL induces IL-8 production and by which PPARalpha activation abolishes LDL effects in human aortic SMCs (hAoSMCs). Herein is the first report of PPARgamma activation by troglitazone (TG) exerting its inhibitory effects on LDL-induced cell proliferation via generation not of H(2)O(2), but of O2(.-), and the subsequent activation of Erk1/2 in hAoSMCs. Moreover, in this study TG abolished the LDL-accelerated G(1)-S progression to control levels via down-regulation of active cyclinD1/CDK4 and cyclinE/CDK2 complexes and up-regulation of p21(Cip1) expression. TG exerted its anti-proliferative effects through the up-regulation of basal superoxide dismutase (SOD) expression. This data suggests that the regulation of O2(.-) is located at the crossroads between LDL signaling and cell proliferation.
Heo
Kyung-Sun
KS
Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon, Republic of Korea.
Kim
Dong-Uk
DU
Ryoo
Sungwoo
S
Nam
Miyoung
M
Baek
Seung Tae
ST
Kim
Lila
L
Park
Song-Kyu
SK
Myung
Chang-Seon
CS
Hoe
Kwang-Lae
KL
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008077:Lipoproteins, LDL / Q000008:administration & dosage*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D008077:Lipoproteins, LDL; D047495:PPAR gamma; D013481:Superoxides; D013482:Superoxide Dismutase