Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 377, Issue 4, Pages 1042-1046Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2008.10.056
Keywords
Vascular endothelium; Nitric oxide; Argininosuccinate synthase; Phosphorylation; Protein kinase A; Vascular endothelial growth factor
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Funding
- James and Esther King Biomedical Research Program [08KB-01-17237]
- University of South Florida Foundation - Mary and Walter Traskiewicz Memorial Fund
- USF Health Bridge
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Argininosuccinate synthase (AS) is essential for endothelial nitric oxide (NO) production and its regulation in this capacity has been studied primarily at the transcriptional level. The dynamics of vascular function suggest that an acute regulation system may mediate AS function. This premise underlies our hypothesis that AS is phosphorylated in vascular endothelium. Immunoprecipitation and immobilized metal affinity chromatography demonstrated that AS is an endogenous phosphoprotein. An in vitro kinase screen revealed that protein kinase A (PKA), a kinase that enhances NO production via eNOS activation, phosphorylated AS. Vascular endothelial growth factor (VEGF) was identified as a candidate pathway for regulating AS phosphorylation since it enhanced NO production and activated PKA and eNOS. MDLA, diminished maximal VEGF-mediated NO production. In addition, immunoprecipitation an AS inhibitor studies suggested that VEGF enhanced AS phosphorylation. Overall, these results represent the first demonstration that vascular endothelial NO production can be regulated by dynamic AS phosphorylation. (C) 2008 Elsevier Inc. All rights reserved.
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