Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin
Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin
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DOI：
10.1152/ajpheart.00248.2004
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发表时间：
2004-12-01
影响因子：
4.8
通讯作者：
Katusic, ZS
中科院分区：
文献类型：
--
作者：
Blackwell, KA;Sorenson, JP;Katusic, ZS
氧化应激是衰老诱导血管内皮功能障碍的重要机制。以往的研究表明，四氢生物蝶呤（BH 4），内皮细胞NO合酶的一个重要的辅因子，可能是一个氧化的分子靶点。我们检验了氧化应激，特别是BH 4的氧化，可能有助于老年小鼠内皮依赖性舒张功能减弱的假设。应用视频图像分析仪对离体颈动脉血管功能进行研究。通过HPLC测量BH 4及其氧化产物的血管水平。老年小鼠（年龄，95+/-2周），对ACh（10（-5）至10（-9）M）的内皮依赖性舒张以及对NO供体二乙基铵（Z）-1-（N，N-二乙基氨基）二氮烯-1，2-二醇盐（DEA-NONOate，10（-5）至10（-9）M）与在年轻小鼠（年龄，23+/-0.5周）中检测到的松弛相比显著降低。用可渗透细胞的SOD模拟物Mn（III）四（4-苯甲酸）卟啉氯化物孵育老年小鼠颈动脉，使ACh和DEA-NONOate的舒张正常化。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-反应蛋白的小鼠类似物）的血清水平增加。在主动脉中，无论是BH_4的浓度还是还原BH_4与氧化产物的比值，在青年和老年小鼠之间都没有差异。我们的研究结果表明，在小鼠中，衰老损害松弛介导的NO最有可能通过增加超氧阴离子的形成。BH 4的氧化似乎不是老年小鼠动脉血管功能障碍的重要机制。
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.