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首页> 外文期刊>American Journal of Physiology >Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin.
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Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin.

机译：衰老诱导的内皮依赖性舒张损害的机制：四氢生物蝶呤的作用。

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摘要

Oxidative stress has been implicated as an important mechanism of vascular endothelial dysfunction induced by aging. Previous studies suggested that tetrahydrobiopterin (BH4), an essential cofactor of endothelial NO 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 relaxation in aged mice. Vasomotor function of isolated carotid arteries was studied using a video dimension analyzer. Vascular levels of BH4 and its oxidation products were measured via HPLC. In aged mice (age, 95 +/- 2 wk), endothelium-dependent relaxation to ACh (10(-5) to 10(-9) M) as well as endothelium-independent relaxation to the NO donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-5) to 10(-9) M) were significantly reduced compared with relaxation detected in young mice (age, 23 +/- 0.5 wk). Incubation of aged mouse carotid arteries with the cell-permeable SOD mimetic Mn(III)tetra(4-benzoic acid)porphyrin chloride normalized relaxation to ACh and DEA-NONOate. Furthermore, production of superoxide anion in aorta and serum levels of amyloid P component, which is the murine analog of C-reactive protein, was 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 relaxation mediated by NO most likely by increased formation of superoxide anion. Oxidation of BH4 does not appear to be an important mechanism underlying vasomotor dysfunction in aged mouse arteries.
机译：氧化应激被认为是衰老引起的血管内皮功能障碍的重要机制。先前的研究表明，四氢生物蝶呤（BH4）是内皮一氧化氮合酶的必要辅助因子，可能是氧化的分子靶标。我们测试了氧化应激，尤其是BH4的氧化，可能有助于衰老小鼠的内皮依赖性舒张减弱的假说。使用视频尺寸分析仪研究了孤立的颈动脉的血管舒缩功能。通过HPLC测量BH 4及其氧化产物的血管水平。在老年小鼠（年龄95 +/- 2 wk）中，内皮依赖性舒张至ACh（10（-5）至10（-9）M），以及内皮依赖性舒张至NO供体二乙铵（Z）- 1-（N，N-二乙基氨基）重氮-1-1,2-二醇盐（DEA-NONOate，10（-5）至10（-9）M）与年轻小鼠（年龄）的放松相比明显降低，23 +/- 0.5 wk）。用细胞可渗透的SOD模拟Mn（III）四（4-苯甲酸）卟啉氯化物温育小鼠颈动脉，使ACh和DEA-NONOate的松弛作用正常化。此外，在老年小鼠中，主动脉中超氧阴离子的产生和淀粉样蛋白P组分（C反应蛋白的鼠类类似物）的血清水平增加。在主动脉中，年轻和老年小鼠的BH4浓度或还原的BH4与氧化产物的比率均无差异。我们的研究结果表明，在小鼠中，衰老会损害由NO介导的松弛，这很可能是由于超氧阴离子形成的增加。在衰老的小鼠动脉中，BH4的氧化似乎不是引起血管舒缩功能障碍的重要机制。

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