Signal transducer and activator of transcription 3α and specificity protein 1 interact to upregulate intercellular adhesion molecule-1 in ischemic-reperfused myocardium and vascular endothelium

Xiao Ping Yang, Kaikobad Irani, Subhendra Mattagajasingh, Anthony Dipaula, Firdous Khanday, Michitaka Ozaki, Karen Fox-Talbot, William M. Baldwin, Lewis Becker

Research output: Contribution to journalArticle

Abstract

Objective-Intercellular adhesion molecule-1 (ICAM-1) is upregulated rapidly on endothelial cells during ischemia-reperfusion (I-R) and mediates tissue leukocyte accumulation. The ICAM-1 proximal promoter contains a signal transducer and activator of transcription (Stat) binding motif (gamma-interferon activation site [GAS] sequence), which flanks a specificity protein 1 (Sp1) binding site. We examined the roles of Stat and Sp1 in the regulation of ICAM-1 after myocardial I-R. Methods and Results-Open-chest anesthetized rats underwent coronary artery occlusion for 35 minutes and reperfusion for 0 to 240 minutes. Stat became activated within 15 minutes after reperfusion, primarily in vascular endothelial cells; the activated Stat protein was identified as Stat3 (α-isoform). After phosphorylation on serine 727 (p-S727), Stat3α was found in association with the transcriptional regulator Sp1, and the complex bound to an ICAM-1-GAS probe. ICAM-1 expression increased after I-R and lagged shortly behind Stat3α activation. In cultured human umbilical vein endothelial (HUVE) cells, activation of Stat3α after hypoxia-reoxygenation (H-R) was dependent on the small GTPase Rac1. Transfection of a dominant-negative Stat3 (Y705F) adenovirus or a GAS decoy oligonucleotide reduced ICAM-1 mRNA expression after H-R. Using a reporter gene transfected into HUVE cells, mutation of the GAS element in the ICAM-1 promoter resulted in reduced transcriptional activity after H-R. Sp1 coimmunoprecipitated with p-S727 Stat3 during H-R, and Sp1 or Stat3α interfering RNA markedly reduced ICAM-1 mRNA expression. Conclusion-The Sp1-Stat3 complex appears to play an important role in the upregulation of ICAM-1 transcription after reoxygenation or reperfusion.

Original languageEnglish (US)
Pages (from-to)1395-1400
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 2005

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Keywords

  • Adhesion molecule
  • Endothelial cell
  • Ischemia-reperfusion
  • Myocardium
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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