title: Erythropoietin prevents endothelial dysfunction in GTP-cyclohydrolase I-deficient hph1 mice.
abstract: : In this study, we used the mutant hph1 mouse model, which has deficiency in GTP-cyclohydrolase I (GTPCH I) activity, to test the hypothesis that erythropoietin (EPO) protects aortic wall from oxidative stress induced by uncoupling of endothelial nitric oxide synthase (eNOS). Both GTPCH I activity and tetrahydrobiopterin (BH4) levels were reduced in hph1 mice, whereas 7,8-dihydrobiopterin (7,8-BH2) levels were significantly increased. Furthermore, BH4 deficiency caused increased production of superoxide anion and hydrogen peroxide in the aorta thus resulting in impairment of endothelium-dependent relaxations to acetylcholine. Treatment of hph1 mice with recombinant human EPO (1000 U/kg, subcutaneously for 3 days) significantly decreased superoxide anion production by eNOS and improved BH4 to 7,8-BH2 ratio in aortas. EPO also significantly decreased production of hydrogen peroxide and improved endothelium-dependent relaxations in aortas of hph1 mice. In addition, EPO treatment increased protein expressions of copper-/zinc-superoxide dismutase, manganese-superoxide dismutase, and catalase in the aorta of hph1 mice. Our findings demonstrate that treatment with EPO prevented oxidative stress and endothelial dysfunction caused by eNOS uncoupling. Increased vascular expressions of antioxidants seem to be an important molecular mechanism underlying vascular protection by EPO during chronic BH4 deficiency.
authors.affiliation: Departments of *Anesthesiology; and †Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Livius V
authors.initials: LV
authors.lastname: dʼUscio
authors.forename: Anantha V R
authors.initials: AV
authors.lastname: Santhanam
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000494:pharmacology*; D006136:GTP Cyclohydrolase / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D011994:Recombinant Proteins; D013481:Superoxides; D004921:Erythropoietin; D001708:Biopterins; D000068817:Epoetin Alfa; C017226:7,8-dihydrobiopterin; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; D000109:Acetylcholine