Reactive Oxygen Species (ROS) Mediate p300-dependent STAT1 Protein Interaction with Peroxisome Proliferator-activated Receptor (PPAR)-γ in CD36 Protein Expression and Foam Cell Formation.
Previously, we have demonstrated that 15(S)-hydroxyeicosatetranoic acid (15(S)-HETE) induces CD36 expression involving STAT1. Many studies have shown that peroxisome proliferator-activated receptor (PPAR)-γ mediates CD36 expression. Therefore, we asked the question whether these transcriptional factors interact with each other in the regulation of CD36 expression by 15(S)-HETE. Here, we show that STAT1 interacts with PPARγ in the induction of CD36 expression and foam cell formation by 15(S)-HETE. In addition, using molecular biological approaches such as EMSA, supershift EMSA, ChIP, re-ChIP, and promoter-reporter gene assays, we demonstrate that the STAT1 and PPARγ complex binds to the STAT-binding site at -107 nucleotides in the CD36 promoter and enhances its activity. Furthermore, the interaction of STAT1 with PPARγ depends on STAT1 acetylation, which is mediated by p300. In addition, our findings show that reactive oxygen species-dependent Syk and Pyk2 stimulation is required for p300 tyrosine phosphorylation and activation. Together, these results demonstrate that an interaction between STAT1, p300, and peroxisome proliferator-activated receptor-γ is required for 15(S)-HETE-induced CD36 expression, oxidized low density lipoprotein uptake, and foam cell formation, critical events underlying the pathogenesis of atherosclerosis.
From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Sivareddy
S
Kotla
From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 rgadipar@uthsc.edu.
Gadiparthi N
GN
Rao
D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000378:metabolism*
D018955:CD36 Antigens; D006893:Hydroxyeicosatetraenoic Acids; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
15(S)-HETE; cd36; foam cell; gene expression; lipid; lipoxygenase pathway; peroxisome proliferator-activated receptor (PPAR); signal transducers and activators of transcription 1 (STAT1)