Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease.
Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease.
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DOI：
10.1016/j.niox.2011.04.004
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发表时间：
2011-08-01
期刊：
影响因子：
--
通讯作者：
Channon KM
中科院分区：
文献类型：
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作者：
Crabtree MJ;Channon KM
一氧化氮是由一氧化氮合酶（NOS）产生的，在心血管稳态和心血管疾病的发病中起着关键作用。NOS辅助因子四氢生物蝶呤（BH4）是NOS功能的重要调节因子，因为BH4需要维持l-精氨酸氧化的酶偶联以产生NO。BH4的损失或氧化为7,8-二氢生物蝶呤（BH2）与NOS解偶联有关，导致产生超氧化物而不是NO。除了在叶酸代谢中起关键作用外，二氢叶酸还原酶（DHFR）还可以“回收”BH2，从而再生BH4。因此，净BH4细胞生物利用度很可能反映了BH4的新合成、氧化为BH2的BH4损失和DHFR对BH4的再生之间的平衡。最近的研究表明BH4再循环直接调控eNOS解偶联，表明即使在没有氧化应激的情况下，使用dhfr特异性siRNA和甲氨蝶呤处理抑制BH4再循环也会导致内皮细胞和BH4缺乏的hph-1小鼠模型中的eNOS解偶联。这些研究表明，BH4水平和调控BH4生物利用度的循环途径都是潜在的治疗靶点，本文将对此进行讨论。
Nitric oxide, generated by the nitric oxide synthase (NOS) enzymes, plays pivotal roles in cardiovascular homeostasis and in the pathogenesis of cardiovascular disease. The NOS cofactor, tetrahydrobiopterin (BH4), is an important regulator of NOS function, since BH4 is required to maintain enzymatic coupling of l-arginine oxidation, to produce NO. Loss or oxidation of BH4 to 7,8-dihydrobiopterin (BH2) is associated with NOS uncoupling, resulting in the production of superoxide rather than NO. In addition to key roles in folate metabolism, dihydrofolate reductase (DHFR) can ‘recycle’ BH2, and thus regenerate BH4. It is therefore likely that net BH4 cellular bioavailability reflects the balance between de novo BH4 synthesis, loss of BH4 by oxidation to BH2, and the regeneration of BH4 by DHFR. Recent studies have implicated BH4 recycling in the direct regulation of eNOS uncoupling, showing that inhibition of BH4 recycling using DHFR-specific siRNA and methotrexate treatment leads to eNOS uncoupling in endothelial cells and the hph-1 mouse model of BH4 deficiency, even in the absence of oxidative stress. These studies indicate that not only BH4 level, but the recycling pathways regulating BH4 bioavailability represent potential therapeutic targets and will be discussed in this review.