Interferon regulatory factor-1 mediates PPARgamma-induced apoptosis in vascular smooth muscle cells.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPARgamma) possesses general beneficial effects on the cardiovascular system, such as inhibition of vascular lesion formation and atherosclerosis. However, molecular mechanisms for these effects are yet to be fully defined. The aim of this study is to elucidate whether interferon regulatory factor-1 (IRF-1), a transcriptional factor with anti-proliferative and pro-apoptotic properties, mediates PPARgamma-induced apoptosis in vascular smooth muscle cells (VSMCs).


RESULTS
Using Northern and Western blot analyses, we documented that PPARgamma ligands, including ciglitazone, troglitazone, and GW7845, significantly increased IRF-1 expression in VSMCs; however, the PPARalpha ligand (Wy14643) and PPARdelta ligand (GW0742) did not affect its expression. PPARgamma-induced IRF-1 expression was abrogated by pretreatment with the PPARgamma antagonist GW9662. In contrast, adenoviral expression of PPARgamma in VSMCs dramatically increased IRF-1 level. Furthermore, PPARgamma activation increased IRF-1 promoter activity but did not affect IRF-1 mRNA stability. Finally, reducing IRF-1 expression by antisense technology attenuated PPARgamma-induced VSMC apoptosis through decreasing cyclin-dependent kinase inhibitor p21(cip1) and caspase-3 activity.


CONCLUSIONS
Our data demonstrate that IRF-1 is a novel PPARgamma target gene and mediates PPARgamma-induced VSMC apoptosis.
Lin
Yiming
Y
Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA.
Zhu
Xiaojun
X
McLntee
Farron L
FL
Xiao
Hailian
H
Zhang
Jifeng
J
Fu
Mingui
M
Chen
Yuqing E
YE
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000821:virology; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1; D008024:Ligands; D009131:Muscle, Smooth, Vascular / Q000737:chemistry* / Q000378:metabolism* / Q000821:virology; D010080:Oxazoles / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D020871:RNA Stability / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000077288:Troglitazone; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D002839:Chromans; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D008024:Ligands; D010080:Oxazoles; D010750:Phosphoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C401311:GW 7845; D014443:Tyrosine; D000077288:Troglitazone; C039671:ciglitazone