Published ahead of print on June 10, 2004, doi:10.1165/rcmb.2004-0098OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 3, September 2004, 365-372 A more recent version of this article appeared on September 1, 2004
Submitted on March 22, 2004 Src Kinase Mediates Angiotensin II-Dependent Increase in Pulmonary Endothelial Nitric Oxide SynthaseXinmei Li1,1 Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA, 2 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA * To whom correspondence should be addressed. E-mail: susan_olson{at}nymc.edu.
We have previously demonstrated that angiotensin II stimulates nitric oxide production in bovine pulmonary artery endothelial cells (BPAECs) by increasing nitric oxide synthase (eNOS) expression via the type 2 receptor. The purpose of this study was to identify the angiotensin II-dependent signaling pathway that mediates this increase in eNOS. The angiotensin II-dependent increase in eNOS expression is prevented when BPAECs are pretreated with the tyrosine kinase inhibitors, herbimycin A and PP2. PP2 also blocked angiotensin II-dependent MEK-1 and MAPK phosphorylation, suggesting that Src is upstream of MAPK in this pathway. Transfection of BPAECs with a Src dominant negative mutant cDNA prevented the angiotensin II-dependent Src activation and increase in eNOS protein expression. PD98059, a MEK-1 inhibitor, prevented the angiotensin II-dependent ERK1/ERK2 phosphorylation and increase in eNOS expression. Neither AG1478, an epidermal growth factor receptor kinase inhibitor, nor AG1295, a platelet derived growth factor receptor kinase inhibitor, had any effect on angiotensin II-stimulated Src activity, MAPK activation and eNOS expression. Pertussis toxin prevented the angiotensin II-dependent increase in Src activity, MAPK activation and eNOS expression. This data suggest that angiotensin II stimulates Src tyrosine kinase via a pertussis toxin-sensitive pathway, which, in turn, activates the MAPK pathway resulting in increased eNOS protein expression in BPAECs.
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