Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2004 Feb;112(2):201–206. doi: 10.1289/ehp.6477

Vanadyl sulfate inhibits NO production via threonine phosphorylation of eNOS.

Zhuowei Li 1, Jacqueline D Carter 1, Lisa A Dailey 1, Yuh-Chin T Huang 1
PMCID: PMC1241829  PMID: 14754574

Abstract

Exposure to excessive vanadium occurs in some occupations and with consumption of some dietary regimens for weight reduction and body building. Because vanadium is vasoactive, individuals exposed to excessive vanadium may develop adverse vascular effects. We have previously shown that vanadyl sulfate causes acute pulmonary vasoconstriction, which could be attributed in part to inhibition of nitric oxide production. In the present study we investigated whether NO inhibition was related to phosphorylation of endothelial nitric oxide synthase (eNOS). VOSO4 produced dose-dependent constriction of pulmonary arteries in isolated perfused lungs and pulmonary arterial rings and a right shift of the acetylcholine-dependent vasorelaxation curve. VOSO4 inhibited constitutive as well as A23187-stimulated NO production. Constitutive NO inhibition was accompanied by increased Thr495 (threonine at codon 495) phosphorylation of eNOS, which would inhibit eNOS activity. Thr495 phosphorylation of eNOS and inhibition of NO were partially reversed by pretreatment with calphostin C, a protein kinase C (PKC) inhibitor. There were no changes in Ser1177 (serine at codon 1177) or tyrosine phosphorylation of eNOS. These results indicate that VOSO4 induced acute pulmonary vasoconstriction that was mediated in part by the inhibition of endothelial NO production via PKC-dependent phosphorylation of Thr495 of eNOS. Exposure to excessive vanadium may contribute to pulmonary vascular diseases.

Full Text

The Full Text of this article is available as a PDF (175.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ayajiki K., Kindermann M., Hecker M., Fleming I., Busse R. Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Circ Res. 1996 May;78(5):750–758. doi: 10.1161/01.res.78.5.750. [DOI] [PubMed] [Google Scholar]
  2. Benabe J. E., Cruz-Soto M. A., Martínez-Maldonado M. Critical role of extracellular calcium in vanadate-induced renal vasoconstriction. Am J Physiol. 1984 Mar;246(3 Pt 2):F317–F322. doi: 10.1152/ajprenal.1984.246.3.F317. [DOI] [PubMed] [Google Scholar]
  3. Boo Yong Chool, Sorescu George, Boyd Nolan, Shiojima Ichiro, Walsh Kenneth, Du Jie, Jo Hanjoong. Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A. J Biol Chem. 2001 Nov 29;277(5):3388–3396. doi: 10.1074/jbc.M108789200. [DOI] [PubMed] [Google Scholar]
  4. Borchard U., Greeff K., Hafner D., Noack E., Rojsathaporn K. Effects of vanadate on heart and circulation. J Cardiovasc Pharmacol. 1981 May-Jun;3(3):510–521. doi: 10.1097/00005344-198105000-00010. [DOI] [PubMed] [Google Scholar]
  5. Brouet A., Sonveaux P., Dessy C., Balligand J. L., Feron O. Hsp90 ensures the transition from the early Ca2+-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells. J Biol Chem. 2001 Jun 25;276(35):32663–32669. doi: 10.1074/jbc.M101371200. [DOI] [PubMed] [Google Scholar]
  6. Bu-Olayan A. H., al-Yakoob S. Lead, nickel and vanadium in seafood: an exposure assessment for Kuwaiti consumers. Sci Total Environ. 1998 Nov 10;223(2-3):81–86. doi: 10.1016/s0048-9697(98)00213-7. [DOI] [PubMed] [Google Scholar]
  7. Cadène A., Grigorescu F., Serrano J. J., Cros G. Characterization of vanadyl sulfate effect on vascular contraction: roles of calcium and tyrosine phosphorylation. J Pharmacol Exp Ther. 1997 Apr;281(1):491–498. [PubMed] [Google Scholar]
  8. Chen Z. P., Mitchelhill K. I., Michell B. J., Stapleton D., Rodriguez-Crespo I., Witters L. A., Power D. A., Ortiz de Montellano P. R., Kemp B. E. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999 Jan 29;443(3):285–289. doi: 10.1016/s0014-5793(98)01705-0. [DOI] [PubMed] [Google Scholar]
  9. Chen Z., Yuhanna I. S., Galcheva-Gargova Z., Karas R. H., Mendelsohn M. E., Shaul P. W. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999 Feb;103(3):401–406. doi: 10.1172/JCI5347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Corson M. A., James N. L., Latta S. E., Nerem R. M., Berk B. C., Harrison D. G. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res. 1996 Nov;79(5):984–991. doi: 10.1161/01.res.79.5.984. [DOI] [PubMed] [Google Scholar]
  11. Dimmeler S., Dernbach E., Zeiher A. M. Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett. 2000 Jul 21;477(3):258–262. doi: 10.1016/s0014-5793(00)01657-4. [DOI] [PubMed] [Google Scholar]
  12. Fleming I., Fisslthaler B., Dimmeler S., Kemp B. E., Busse R. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res. 2001 Jun 8;88(11):E68–E75. doi: 10.1161/hh1101.092677. [DOI] [PubMed] [Google Scholar]
  13. Fulton D., Gratton J. P., McCabe T. J., Fontana J., Fujio Y., Walsh K., Franke T. F., Papapetropoulos A., Sessa W. C. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999 Jun 10;399(6736):597–601. doi: 10.1038/21218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fulton D., Gratton J. P., Sessa W. C. Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J Pharmacol Exp Ther. 2001 Dec;299(3):818–824. [PubMed] [Google Scholar]
  15. García-Cardeña G., Fan R., Stern D. F., Liu J., Sessa W. C. Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem. 1996 Nov 1;271(44):27237–27240. doi: 10.1074/jbc.271.44.27237. [DOI] [PubMed] [Google Scholar]
  16. Govers R., Rabelink T. J. Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol. 2001 Feb;280(2):F193–F206. doi: 10.1152/ajprenal.2001.280.2.F193. [DOI] [PubMed] [Google Scholar]
  17. Harris M. B., Ju H., Venema V. J., Liang H., Zou R., Michell B. J., Chen Z. P., Kemp B. E., Venema R. C. Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem. 2001 Feb 28;276(19):16587–16591. doi: 10.1074/jbc.M100229200. [DOI] [PubMed] [Google Scholar]
  18. Hauser R., Eisen E. A., Pothier L., Christiani D. C. A prospective study of lung function among boilermaker construction workers exposed to combustion particulates. Am J Ind Med. 2001 May;39(5):454–462. doi: 10.1002/ajim.1039. [DOI] [PubMed] [Google Scholar]
  19. Hauser R., Elreedy S., Hoppin J. A., Christiani D. C. Airway obstruction in boilermakers exposed to fuel oil ash. A prospective investigation. Am J Respir Crit Care Med. 1995 Nov;152(5 Pt 1):1478–1484. doi: 10.1164/ajrccm.152.5.7582280. [DOI] [PubMed] [Google Scholar]
  20. Hauser R., Elreedy S., Ryan P. B., Christiani D. C. Urine vanadium concentrations in workers overhauling an oil-fired boiler. Am J Ind Med. 1998 Jan;33(1):55–60. doi: 10.1002/(sici)1097-0274(199801)33:1<55::aid-ajim7>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  21. Hauser Russ, Eisen Ellen A., Pothier Lucille, Lewis Daniel, Bledsoe Toni, Christiani David C. Spirometric abnormalities associated with chronic bronchitis, asthma, and airway hyperresponsiveness among boilermaker construction workers. Chest. 2002 Jun;121(6):2052–2060. doi: 10.1378/chest.121.6.2052. [DOI] [PubMed] [Google Scholar]
  22. Hessel P. A., Melenka L. S., Michaelchuk D., Herbert F. A., Cowie R. L. Lung health among boilermakers in Edmonton, Alberta. Am J Ind Med. 1998 Oct;34(4):381–386. doi: 10.1002/(sici)1097-0274(199810)34:4<381::aid-ajim12>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  23. Hirao T. Redox reactions via vanadium-induced electron transfer. J Inorg Biochem. 2000 May 30;80(1-2):27–33. doi: 10.1016/s0162-0134(00)00036-2. [DOI] [PubMed] [Google Scholar]
  24. Hisamoto K., Ohmichi M., Kanda Y., Adachi K., Nishio Y., Hayakawa J., Mabuchi S., Takahashi K., Tasaka K., Miyamoto Y. Induction of endothelial nitric-oxide synthase phosphorylation by the raloxifene analog LY117018 is differentially mediated by Akt and extracellular signal-regulated protein kinase in vascular endothelial cells. J Biol Chem. 2001 Oct 10;276(50):47642–47649. doi: 10.1074/jbc.M103853200. [DOI] [PubMed] [Google Scholar]
  25. Huang Y. C., Fisher P. W., Nozik-Grayck E., Piantadosi C. A. Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury. Am J Physiol. 1997 Sep;273(3 Pt 1):L504–L512. doi: 10.1152/ajplung.1997.273.3.L504. [DOI] [PubMed] [Google Scholar]
  26. Huang Yuh-Chin T., Wu Weidong, Ghio Andrew J., Carter Jacqueline D., Silbajoris Robert, Devlin Robert B., Samet James M. Activation of EGF receptors mediates pulmonary vasoconstriction induced by residual oil fly ash. Exp Lung Res. 2002 Jan-Feb;28(1):19–38. doi: 10.1080/019021402753355517. [DOI] [PubMed] [Google Scholar]
  27. Kumar A., Corder C. N. Diuretic and vasoconstrictor effects of sodium orthovanadate on the isolated perfused rat kidney. J Pharmacol Exp Ther. 1980 Apr;213(1):85–90. [PubMed] [Google Scholar]
  28. Larsen J. A., Thomsen O. O. Vanadate-induced oliguria and vasoconstriction in the cat. Acta Physiol Scand. 1980 Dec;110(4):367–374. doi: 10.1111/j.1748-1716.1980.tb06682.x. [DOI] [PubMed] [Google Scholar]
  29. Levy B. S., Hoffman L., Gottsegen S. Boilermakers' bronchitis. Respiratory tract irritation associated with vanadium pentoxide exposure during oil-to-coal conversion of a power plant. J Occup Med. 1984 Aug;26(8):567–570. [PubMed] [Google Scholar]
  30. Linehan J. H., Dawson C. A., Rickaby D. A. Distribution of vascular resistance and compliance in a dog lung lobe. J Appl Physiol Respir Environ Exerc Physiol. 1982 Jul;53(1):158–168. doi: 10.1152/jappl.1982.53.1.158. [DOI] [PubMed] [Google Scholar]
  31. Liochev S., Fridovich I. The oxidation of NADH by tetravalent vanadium. Arch Biochem Biophys. 1987 Jun;255(2):274–278. doi: 10.1016/0003-9861(87)90394-8. [DOI] [PubMed] [Google Scholar]
  32. Magari Shannon R., Schwartz Joel, Williams Paige L., Hauser Russ, Smith Thomas J., Christiani David C. The association of particulate air metal concentrations with heart rate variability. Environ Health Perspect. 2002 Sep;110(9):875–880. doi: 10.1289/ehp.02110875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Michell B. J., Chen Zp, Tiganis T., Stapleton D., Katsis F., Power D. A., Sim A. T., Kemp B. E. Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem. 2001 Apr 5;276(21):17625–17628. doi: 10.1074/jbc.C100122200. [DOI] [PubMed] [Google Scholar]
  34. Michell B. J., Griffiths J. E., Mitchelhill K. I., Rodriguez-Crespo I., Tiganis T., Bozinovski S., de Montellano P. R., Kemp B. E., Pearson R. B. The Akt kinase signals directly to endothelial nitric oxide synthase. 1999 Jul 29-Aug 12Curr Biol. 9(15):845–848. doi: 10.1016/s0960-9822(99)80371-6. [DOI] [PubMed] [Google Scholar]
  35. Montagnani M., Chen H., Barr V. A., Quon M. J. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem. 2001 Jun 11;276(32):30392–30398. doi: 10.1074/jbc.M103702200. [DOI] [PubMed] [Google Scholar]
  36. Nechay B. R. Mechanisms of action of vanadium. Annu Rev Pharmacol Toxicol. 1984;24:501–524. doi: 10.1146/annurev.pa.24.040184.002441. [DOI] [PubMed] [Google Scholar]
  37. Nechay B. R., Nanninga L. B., Nechay P. S. Vanadyl (IV) and vanadate (V) binding to selected endogenous phosphate, carboxyl, and amino ligands; calculations of cellular vanadium species distribution. Arch Biochem Biophys. 1986 Nov 15;251(1):128–138. doi: 10.1016/0003-9861(86)90059-7. [DOI] [PubMed] [Google Scholar]
  38. Papapetropoulos A., García-Cardeña G., Madri J. A., Sessa W. C. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest. 1997 Dec 15;100(12):3131–3139. doi: 10.1172/JCI119868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ramanadham S., Heyliger C., Gresser M. J., Tracey A. S., McNeill J. H. The distribution and half-life for retention of vanadium in the organs of normal and diabetic rats orally fed vanadium(IV) and vanadium(V). Biol Trace Elem Res. 1991 Aug;30(2):119–124. doi: 10.1007/BF02990348. [DOI] [PubMed] [Google Scholar]
  40. Ryan J. W., Day A. R., Schultz D. R., Ryan U. S., Chung A., Marlborough D. I., Dorer F. E. Localization of angiotensin converting enzyme (kininase II). I. Preparation of antibody-hemeoctapeptide conjugates. Tissue Cell. 1976;8(1):111–124. doi: 10.1016/0040-8166(76)90024-0. [DOI] [PubMed] [Google Scholar]
  41. Ryan U. S., Ryan J. W., Whitaker C., Chiu A. Localization of angiotensin converting enzyme (kininase II). II. Immunocytochemistry and immunofluorescence. Tissue Cell. 1976;8(1):125–145. doi: 10.1016/0040-8166(76)90025-2. [DOI] [PubMed] [Google Scholar]
  42. Schnyder Bruno, Pittet Martine, Durand Jacques, Schnyder-Candrian Silvia. Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport. Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E87–E94. doi: 10.1152/ajpendo.00050.2001. [DOI] [PubMed] [Google Scholar]
  43. Susić D., Kentera D. Effect of chronic vanadate administration on pulmonary circulation in the rat. Respiration. 1986;49(1):68–72. doi: 10.1159/000194861. [DOI] [PubMed] [Google Scholar]
  44. Teissèdre P. L., Krosniak M., Portet K., Gasc F., Waterhouse A. L., Serrano J. J., Cabanis J. C., Cros G. Vanadium levels in French and Californian wines: influence on vanadium dietary intake. Food Addit Contam. 1998 Jul;15(5):585–591. doi: 10.1080/02652039809374685. [DOI] [PubMed] [Google Scholar]
  45. Woodin M. A., Hauser R., Liu Y., Smith T. J., Siegel P. D., Lewis D. M., Tollerud D. J., Christiani D. C. Molecular markers of acute upper airway inflammation in workers exposed to fuel-oil ash. Am J Respir Crit Care Med. 1998 Jul;158(1):182–187. doi: 10.1164/ajrccm.158.1.9711054. [DOI] [PubMed] [Google Scholar]
  46. Woodin M. A., Liu Y., Hauser R., Smith T. J., Christiani D. C. Pulmonary function in workers exposed to low levels of fuel-oil ash. J Occup Environ Med. 1999 Nov;41(11):973–980. doi: 10.1097/00043764-199911000-00009. [DOI] [PubMed] [Google Scholar]
  47. Woodin M. A., Liu Y., Neuberg D., Hauser R., Smith T. J., Christiani D. C. Acute respiratory symptoms in workers exposed to vanadium-rich fuel-oil ash. Am J Ind Med. 2000 Apr;37(4):353–363. doi: 10.1002/(sici)1097-0274(200004)37:4<353::aid-ajim5>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES