Published online before print August 4, 2005, doi: 10.1161/01.RES.0000179775.04114.45
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Submitted on March 17, 2005
Revised on June 28, 2005
Accepted on July 21, 2005
PKC
Activates eNOS and Increases Arterial Blood Flow In Vivo
Chohreh Partovian ;
From the Angiogenesis Research Center and Section of Cardiology (C.P., Z.Z., K.M., M.S.), Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH; the Molecular Cardiology/Whitaker Cardiovascular Institute (M.L., W.C.S.), Boston University School of Medicine, Mass; and the Department of Pharmacology and Molecular Cardiobiology Program (N.O., K.W.), Yale University School of Medicine, New Haven, Conn.
* To whom correspondence should be addressed. E-mail: michael.simons{at}dartmouth.edu.
Endothelial nitric oxide synthase (eNOS) plays an important role in control of vascular tone and angiogenesis among other functions. Its regulation is complex and has not been fully established. Several studies have emphasized the importance of phosphorylation in the regulation of eNOS activity. Although it is commonly accepted that protein kinase C (PKC) signaling inhibits eNOS activity by phosphorylating Thr497 and dephosphorylating Ser1179, the distinct role of different PKC isoforms has not been studied so far. The PKC family comprises roughly 12 different isozymes that activate distinct downstream pathways. The present study was designed to investigate the role of PKC
isoform in regulation of eNOS activity. Overexpression of PKC in primary endothelial cells was associated with increased eNOS-Ser1179 phosphorylation and increased NO production. Inhibition of PKC activity either by siRNA transfection or by overexpression of a dominant negative mutant resulted in a marked decrease in FGF2-induced Ser1179 phosphorylation and NO production. In vivo, PKC transduction in rat femoral arteries resulted in a significant increase in the resting blood flow that was suppressed by treatment with L-NAME, an eNOS inhibitor. In conclusion, these data demonstrate for the first time that PKC stimulates NO production in endothelial cells and plays a role in regulation of blood flow in vivo.
Key words: protein kinase C • blood flow • nitric oxide synthase • endothelial cells
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