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* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.
Oxidative stress has been implicated as an important mechanism of vascular endothelial dysfunction induced by aging. Previous studies suggested that tetrahydrobiopterin (BH4), an essential co-factor of endothelial nitric oxide synthase, could be a molecular target for oxidation. We tested the hypothesis that oxidative stress, in particular oxidation of BH4, may contribute to attenuation of endothelium-dependent relaxations in aged mice. Vasomotor function of isolated carotid arteries was studied by video dimension analyzer. Vascular levels of BH4 and its oxidation products were measured by high performance liquid chromatography. In aged mice (95±2 weeks), endothelium-dependent relaxations to acetylcholine (10-5-10-9 M), as well as endothelium-independent relaxations to a nitric oxide donor, DEA-NONOate (10-5-10-9 M), were significantly reduced as compared to relaxations detected in young mice (23±0.5 weeks). Incubation of aged carotid arteries with the cell-permeable superoxide dismutase mimetic Mn(III) tetra(4-benzoic acid)porphyrin chloride (MnTBAP) normalized relaxations to acetylcholine and DEA-NONOate. Furthermore, production of superoxide anion in aorta and serum levels of amyloid P-component (SAP), the murine analogue of C-reactive protein, were increased in old mice. In aorta, neither the concentration of BH4 nor the ratio of reduced BH4 to the oxidation products were different between young and aged mice. Our results demonstrate that, in mice, aging impairs relaxations mediated by nitric oxide most likely by increased formation of superoxide anion. Oxidation of BH4 does not appear to be an important mechanism underlying vasomotor dysfunction in aged arteries.
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