on April 28, 2005
Published online before print April 28, 2005, doi: 10.1161/01.ATV.0000168428.96177.24
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Submitted on November 8, 2004
Accepted on April 20, 2005
Signal Transducer and Activator of Transcription 3
and Specificity Protein 1 Interact to Upregulate Intercellular Adhesion Molecule-1 in Ischemic-Reperfused Myocardium and Vascular Endothelium
Xiao Ping Yang ;
From the Division of Cardiology, Department of Medicine (X.P.Y., K.I., S.M., A.D., F.K., L.C.B.), and Department of Pathology (K.F.-T., W.M.B.), Johns Hopkins University School of Medicine, Baltimore, Md; and Department of Surgery (M.O.), Division of Organ Transplantation and Regenerative Medicine, Hokkaido University Graduate School of Medicine, Japan.
* To whom correspondence should be addressed. E-mail: lbecker{at}mail.jhmi.edu.
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 (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 (
-isoform). After phosphorylation on serine 727 (p-S727), Stat3 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 Stat3 activation. In cultured human umbilical vein endothelial (HUVE) cells, activation of Stat3 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 Stat3 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.
Key words: adhesion molecule • signal transduction • ischemia-reperfusion • myocardium • endothelial cell
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