on April 24, 2003
Published online before print April 24, 2003, doi: 10.1161/01.ATV.0000073314.51987.84
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Submitted on March 6, 2003
Accepted on April 10, 2003
Rapid Activation of Ras by Fluid Flow Is Mediated by G
q and G
Subunits of Heterotrimeric G Proteins in Human Endothelial Cells
Sivaramaprasad Gudi ;
From the Department of Bioengineering (S.G., N.L.M., N.D., J.A.F.) and the School of Medicine (I.H., G.R.B.), University of California at San Diego, La Jolla; the Center for Perinatal Biology (C.R.W.), Loma Linda University, Loma Linda; and the La Jolla Bioengineering Institute (C.R.W., N.L.M., J.A.F.), La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: frangos{at}ljbi.org.
Objective--Temporal gradients in fluid shear stress have been shown to induce a proatherogenic phenotype in endothelial cells. The biomechanical mechanism(s) that enables the endothelium to respond to fluid shear stress requires rapid activation and signal transduction. The small G protein Ras has been identified as an early link between rapid mechanotransduction events and the effects of shear stress on downstream signal-transduction cascades. The aim of this study was to elucidate the upstream mechanotransduction signaling events mediating the rapid activation of Ras by fluid shear stress in human endothelial cells.
Methods and Results--Direct measurement of Ras-bound GTP and GDP showed that fluid-flow activation of Ras was rapid (10-fold within 5 seconds) and dose dependent on shear stress magnitude. Treatment with protein tyrosine kinase inhibitors or pertussis toxin did not significantly affect flow-induced Ras activation. However, activation was inhibited by transient transfection with antisense to G
q or the G
scavenger -adrenergic receptor kinase carboxy terminus. Transfection with several G subunit isoforms revealed flow-induced Ras activation was most effectively enhanced by G12.
Conclusions--These results suggest that the rapid, shear-induced activation of Ras is mediated by Gq through the activity of G subunits in human vascular endothelial cells.
Key words: endothelium • Ras • G proteins • shear stress
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