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VANADYL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF ENOS
Citation:
Li, Z., J D. Carter, L. A. Dailey, J M. Soukup, AND Huang, YuhChin T. VANADYL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF ENOS. Presented at American Thoracic Society Meeting, Seattle, WA, May 16-21, 2003.
Description:
VANADYL SULFATE INHIBITS NO PRODUCTION BY DIFFERENTIALLY REGULATING SERINE/THREONINE PHOSPHORYLATION OF eNOS.
Zhuowei Li, Jacqueline D. Carter, Lisa A. Dailey, Joleen Soukup, Yuh-Chin T. Huang. CEMALB, University of North Carolina and NHEERL, US EPA, Chapel Hill, North Carolina
Vanadium is a trace element essential for metabolic homeostasis. Exposure to excessive vanadium may occur in occupational settings, with inhalation of ambient particulate matter (PM) and consumption of certain diet regimens. We showed previously that vanadyl sulfate (V) causes pulmonary arterial vasoconstriction, which could be attributed in part to inhibition of NO production, but the mechanisms are unclear. The present study tested the hypothesis that V-induced inhibition of NO production was mediated by altering serine(Ser)/threonine(Thr) phosphorylation of eNOS. V (0.5- 50 microM) produced a dose-dependent constriction of rat pulmonary artery ring and attenuated acetylcholine-dependent vasorelaxation. Cultured human pulmonary artery endothelial cells incubated with V (50 microM) for 5, 10 and 20min showed inhibition of NO production. This was accompanied by an increase in Thr-495 phosphorylation and a decrease in Ser-1177 phosphorylation of eNOS, which would inhibit eNOS activity. The changes in Thr/Ser phosphorylation of eNOS were reversed by pretreatment with calphostin C, a protein kinase C inhibitor, which was accompanied by increased NO production. V had no effect on Ser phosphorylation of Akt. Pretreatment with losartan, an angiotensin-2 receptor (AT2) antagonist, did not affect V-induced eNOS phosphorylation. These results indicate that V inhibited NO production by dephosphorylating Ser-1177 and phosphorylating Thr-495 residues of eNOS critical for its activity. The signaling pathways were partially mediated by protein kinase C, but not Akt or AT2. These results also raise the possibility that exposure to vanadium may produce pulmonary hypertension. (This abstract does not reflect EPA policy).