期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 301, 期 3, 页码 H721-H729出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01089.2010
关键词
tetrahydrobiopterin; sepiapterin; methotrexate; endothelial function; superoxide
资金
- Grants-in-Aid for Scientific Research [23790300, 23590305] Funding Source: KAKEN
Noguchi K, Hamadate N, Matsuzaki T, Sakanashi M, Nakasone J, Uchida T, Arakaki K, Kubota H, Ishiuchi S, Masuzaki H, Sugahara K, Ohya Y, Sakanashi M, Tsutsui M. Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo. Am J Physiol Heart Circ Physiol 301: H721-H729, 2011. First published May 28, 2011; doi:10.1152/ajpheart.01089.2010.-An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH2 in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH2 concentration causes endothelial dysfunction in rats. To increase vascular BH2 levels, the BH2 precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH2 to BH4. MTX/SEP treatment did not significantly affect aortic BH4 levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH2 levels (291.1 +/- 29.2 vs. 33.4 +/- 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH4 levels but decreased the BH4-to-BH2 ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations (P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD (P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH2 causes eNOS dysfunction in vivo even in the absence of BH4 deficiency, demonstrating a novel insight into the regulation of endothelial function.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据