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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1395.)
© 2005 American Heart Association, Inc.

Vascular Biology

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; Kaikobad Irani; Subhendra Mattagajasingh; Anthony DiPaula; Firdous Khanday; Michitaka Ozaki; Karen Fox-Talbot; William M. Baldwin, III; Lewis C. Becker

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.

Correspondence to Dr Lewis C. Becker, Cardiology Division, Halsted 500, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-5500. 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 (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 (-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.

Stat3 was found to upregulate the ICAM-1 gene in ischemia–reperfusion by a novel mechanism. After Rac1-dependent phosphorylation of Stat3, Stat3 bound to Sp1, and the resulting transcriptional complex bound to a GAS sequence in the ICAM-1 proximal promoter. Specific inhibition of Stat3 and/or Sp1 significantly reduced ICAM-1 transcription in hypoxic-reoxygenated endothelial cells.

Key Words: adhesion molecule • signal transduction • ischemia–reperfusion • myocardium • endothelial cell

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