TY - JOUR
T1 - Erythropoietin prevents endothelial dysfunction in GTP-cyclohydrolase I-deficient hph1 mice
AU - D'Uscio, Livius V.
AU - Santhanam, Anantha V.R.
AU - Katusic, Zvonimir S.
N1 - Publisher Copyright:
©2014 Lippincott Williams & Wilkins.
PY - 2014/7/7
Y1 - 2014/7/7
N2 - 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.
AB - 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.
KW - Endothelial cells
KW - Erythropoietin
KW - Mouse aorta
KW - Nitric oxide
KW - Tetrahydrobiopterin
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U2 - 10.1097/FJC.0000000000000145
DO - 10.1097/FJC.0000000000000145
M3 - Article
C2 - 25490417
AN - SCOPUS:84918549407
SN - 0160-2446
VL - 64
SP - 514
EP - 521
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 6
ER -