Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice.
Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice.
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DOI：
10.1161/circresaha.111.261750
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发表时间：
2012-10-12
影响因子：
20.1
通讯作者：
Rudic RD
中科院分区：
文献类型：
--
作者：
Anea CB;Cheng B;Sharma S;Kumar S;Caldwell RW;Yao L;Ali MI;Merloiu AM;Stepp DW;Black SM;Fulton DJ;Rudic RD
小鼠生物钟的破坏产生血管功能障碍，如内皮依赖性信号传导、血管舒缩和血管重塑的损伤所证明的。虽然内皮NO合酶的功能改变和活性氧的过度产生是内皮功能障碍的核心，但迄今为止，昼夜节律钟对内皮NO合酶偶联和血管活性氧产生的影响尚不清楚。本研究的目的是确定是否删除的生物钟的一个关键组成部分，Bmal 1，可以影响内皮NO合酶偶联和活性氧在动脉Bmal 1基因敲除（KO）小鼠的水平。内皮功能降低Bmal 1-KO小鼠的血小板和改善清除活性氧与聚乙二醇-超氧化物歧化酶和非选择性抑制环氧合酶异构体与吲哚美辛。从Bmal 1-KO小鼠的主动脉表现出增强的超氧化物水平测定的电子顺磁共振光谱和二氢乙锭荧光，海拔被废除的硝基-L-精氨酸甲酯的管理。高效液相色谱分析显示，Bmal 1-KO小鼠的肺和主动脉中四氢生物蝶呤减少，二氢生物蝶呤水平增加，而补充四氢生物蝶呤改善了昼夜节律钟KO小鼠的内皮功能。此外，四氢生物蝶呤，二氢生物蝶呤，和调节生物蝶呤生物利用度的关键酶，GTP环化水解酶和二氢叶酸还原酶的水平表现出昼夜节律的表达模式。在葡萄糖和脂质的代谢控制中具有确定的影响，在此，我们描述了生物钟在生物喋呤代谢中的新作用，其在脉管系统中具有显著影响，以调节内皮NO合酶的偶联、超氧化物的产生和内皮功能的维持。(Circ Res. 2012; 111：1157-1165）。
Disruption of the circadian clock in mice produces vascular dysfunction as evidenced by impairments in endothelium-dependent signaling, vasomotion, and blood vessel remodeling. Although the altered function of endothelial NO synthase and the overproduction of reactive oxygen species are central to dysfunction of the endothelium, to date, the impact of the circadian clock on endothelial NO synthase coupling and vascular reactive oxygen species production is not known. The goals of the present study were to determine whether deletion of a critical component of the circadian clock, Bmal1, can influence endothelial NO synthase coupling and reactive oxygen species levels in arteries from Bmal1-knockout (KO) mice. Endothelial function was reduced in aortae from Bmal1-KO mice and improved by scavenging reactive oxygen species with polyethylene glycol-superoxide dismutase and nonselectively inhibiting cyclooxygenase isoforms with indomethacin. Aortae from Bmal1-KO mice exhibited enhanced superoxide levels as determined by electron paramagnetic resonance spectroscopy and dihydroethidium fluorescence, an elevation that was abrogated by administration of nitro-L -arginine methyl ester. High-performance liquid chromatography analysis revealed a reduction in tetrahydrobiopterin and an increase in dihydrobiopterin levels in the lung and aorta of Bmal1-KO mice, whereas supplementation with tetrahydrobiopterin improved endothelial function in the circadian clock KO mice. Furthermore, levels of tetrahydrobiopterin, dihydrobiopterin, and the key enzymes that regulate biopterin bioavailability, GTP cyclohydrolase and dihydrofolate reductase exhibited a circadian expression pattern. Having an established influence in the metabolic control of glucose and lipids, herein, we describe a novel role for the circadian clock in metabolism of biopterins, with a significant impact in the vasculature, to regulate coupling of endothelial NO synthase, production of superoxide, and maintenance of endothelial function. (Circ Res. 2012; 111:1157–1165.)