Erythropoietin prevents endothelial dysfunction in GTP-cyclohydrolase I-deficient hph1 mice

Livius V. D'Uscio, Anantha V.R. Santhanam, Zvonimir S. Katusic

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)514-521
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Issue number6
StatePublished - Jul 7 2014


  • Endothelial cells
  • Erythropoietin
  • Mouse aorta
  • Nitric oxide
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine


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