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. 2004 Sep;31(3):365-72.
doi: 10.1165/rcmb.2004-0098OC. Epub 2004 Jun 10.

Src kinase mediates angiotensin II-dependent increase in pulmonary endothelial nitric oxide synthase

Xinmei Li  1 , Kenneth M Lerea, Jianyu Li, Susan C Olson
Affiliations

Src kinase mediates angiotensin II-dependent increase in pulmonary endothelial nitric oxide synthase

Xinmei Li et al. Am J Respir Cell Mol Biol. 2004 Sep.

Abstract

We have previously demonstrated that angiotensin II (Ang II) stimulates nitric oxide (NO) production in bovine pulmonary artery endothelial cells (BPAECs) by increasing NO synthase (NOS) expression via the type 2 receptor. The purpose of this study was to identify the Ang II-dependent signaling pathway that mediates this increase in endothelial NOS (eNOS). The Ang II-dependent increase in eNOS expression is prevented when BPAECs are pretreated with the tyrosine kinase inhibitors, herbimycin A and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-D]pyrimidine, which also blocked Ang II-dependent mitogen-activated protein kinase (MAPK) kinase/extracellular-regulated protein kinase (MEK)-1 and MAPK phosphorylation, suggesting that Src is upstream of MAPK in this pathway. Transfection of BPAECs with an Src dominant negative mutant cDNA prevented the Ang II-dependent Src activation and increase in eNOS protein expression. PD98059, a MEK-1 inhibitor, prevented the Ang II-dependent phosphorylation of extracellular-regulated protein kinases 1 and 2 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 Ang II-stimulated Src activity, MAPK activation, or eNOS expression. Pertussis toxin prevented the Ang II-dependent increase in Src activity, MAPK activation, and eNOS expression. These data suggest that Ang 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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