Vanadyl sulfate inhibits NO production via threonine phosphorylation of eNOS.
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.
Li
Zhuowei
Z
Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Carter
Jacqueline D
JD
Dailey
Lisa A
LA
Huang
Yuh-Chin T
YC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008168:Lung / Q000502:physiology; D008171:Lung Diseases / Q000209:etiology; D008297:Male; D009569:Nitric Oxide / Q000032:analysis* / Q000737:chemistry*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D016273:Occupational Exposure; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011817:Rabbits; D013912:Threonine / Q000378:metabolism*; D014639:Vanadium / Q000633:toxicity*; D017968:Vanadium Compounds / Q000494:pharmacology* / Q000633:toxicity; D014661:Vasoconstriction
D007004:Hypoglycemic Agents; D017968:Vanadium Compounds; D014639:Vanadium; D013912:Threonine; D009569:Nitric Oxide; C034028:vanadyl sulfate; D019001:Nitric Oxide Synthase