5-Methyltetrahydrofolate and tetrahydrobiopterin can modulate electrotonically mediated endothelium-dependent vascular relaxation
5-Methyltetrahydrofolate and tetrahydrobiopterin can modulate electrotonically mediated endothelium-dependent vascular relaxation
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DOI：
10.1073/pnas.0408919102
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发表时间：
2005-05-10
影响因子：
11.1
通讯作者：
Edwards, DH
中科院分区：
文献类型：
--
作者：
Griffith, TM;Chaytor, AT;Edwards, DH
我们研究了5-甲基四氢叶酸（5-MTHF）和四氢生物蝶呤（BH4）调节一氧化氮（NO）非依赖性血管松弛的能力，这种血管松弛是由内皮超极化通过兔髂动脉壁通过肌内皮和同细胞平滑肌间隙连接的顺序扩散所介导的。间隙连接抑制剂2-氨基乙氧基二苯硼酸盐抑制环吡唑酸引起的松弛和内膜下平滑肌超极化，其作用被5-MTHF和BH4阻止，但被其氧化形式叶酸和7,8-二氢生物蝶呤阻止。类似地，5-MTHF和BH4，而不是叶酸或7,8-二氢生物蝶呤，可以通过靶向Cx37和Cx40的连接素模拟肽（(37,40)Gap 26）和靶向Cx43的肽（(43)Gap 26）减轻内膜下超极化的抑制，从而反映了已知的Cx37和Cx40在兔髂动脉内皮和Cx43介质中的差异表达。2-氨基乙氧基二苯硼酸酯和（37,40）Gap 26对内膜下超极化的抑制作用被过氧化氢酶阻止，过氧化氢酶破坏H2O2。因此，5-MTHF和BH4似乎能够通过减少氧化应激，通过肌内皮和平滑肌间隙连接调节电紧张信号，潜在地通过独立于NO的机制赋予逆转疾病状态下内皮功能障碍的能力。
We have investigated the ability of 5-methyltetrahydrofolate (5-MTHF) and tetrahydrobiopterin (BH4) to modulate nitric oxide (NO)-independent vascular relaxations that are mediated by the sequential spread of endothelial hyperpolarization through the wall of the rabbit iliac artery by means of myoendothelial and homocellular smooth muscle gap junctions. Relaxations and subintimal smooth muscle hyperpolarizations evoked by cyclopiazonic acid were depressed by the gap junction inhibitor 2-aminoethoxy-diphenyl borate, whose effects were prevented by 5-MTHF and BH4, but not by their oxidized forms folic acid and 7,8-dihydro-biopterin. Analogously, 5-MTHF and BH4, but not folic acid or 7,8-dihydrobiopterin, attenuated the depression of subintimal hyperpolarization by a connexin-mimetic peptide targeted against Cx37 and Cx40 ((37,40)Gap 26) and the depression of subadventitial hyperpolarization by a peptide targeted against Cx43 ((43)Gap 26), thus reflecting the known differential expression of Cx37 and Cx40 in the endothelium and Cx43 in the media of the rabbit iliac artery. The inhibitory effects of 2-aminoethoxydiphenyl borate and (37,40)Gap 26 against subintimal hyperpolarization were prevented by catalase, which destroys H2O2. 5-MTHF and BH4 thus appear capable of modulating electrotonic signaling by means of myoendothelial and smooth muscle gap junctions by reducing oxidant stress, potentially conferring an ability to reverse the endothelial dysfunction found in disease states through mechanisms that are independent of NO.