Circulation Research. 2002
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033520.95242.A2
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033520.95242.A2
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Submitted on February 8, 2002
Revised on July 9, 2002
Accepted on July 31, 2002
G
q and Gß
Regulate PAR-1 Signaling of Thrombin-Induced NF-
B Activation and ICAM-1 Transcription in Endothelial Cells
Arshad Rahman *;
From the Department of Pharmacology, College of Medicine, The University of Illinois, Chicago, Ill.
* To whom correspondence should be addressed. E-mail: ARahman{at}uic.edu.
As thrombin binding to the G protein
coupled proteinase activated receptor-1 (PAR-1) induces endothelial adhesivity to leukocytes through NF-B activation and intercellular adhesion molecule-1 (ICAM-1) expression, we determined the signaling pathways mediating the response. Studies showed that the heterotrimeric G proteins, G
q, and the Gß dimer were key determinants of the PAR-1 agonist peptide (TFLLRNPNDK)-induced NF-B activation and ICAM-1 expression in endothelial cells. Cotransfection of RGS3T, a regulator of G-protein signaling that inhibits Gq, or -transducin (Gt), a scavenger of the Gß, markedly decreased NF-B activity induced by PAR-1 activation. We determined the downstream signaling targets activated by Gq and Gß that mediate NF-B activation. Expression of the kinase-defective protein kinase C (PKC)-
mutant inhibited NF-B activation induced by the constitutively active Gq mutant, but had no effect on NF-B activity induced by Gß12. In related experiments, NF-B as well as ICAM-1 promoter activation induced by Gß12 were inhibited by the expression of the dominant-negative mutant of 85-kDa regulatory subunit of PI 3-kinase; however, the expression of this mutant had no effect on the response induced by activated Gq. Cotransfection of the catalytically inactive Akt mutant inhibited the NF-B activation induced by the constitutively active PI 3-kinase mutant as well as that by the activated forms of Gq and PKC-. These results support a model in which ligation of PAR-1 induces NF-B activation and ICAM-1 transcription by the engagement of parallel Gq/PKC- and Gß/PI3-kinase pathways that converge at Akt.
Key words: G proteins • protein kinase C-
•
Akt •
nuclear factor-B •
intercellular adhesion molecule-1 •
endothelial cells
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