Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling.
Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling.
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DOI：
10.1161/circresaha.117.310705
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发表时间：
2017-07-07
影响因子：
20.1
通讯作者：
Straub AC
中科院分区：
文献类型：
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作者：
Rahaman MM;Nguyen AT;Miller MP;Hahn SA;Sparacino-Watkins C;Jobbagy S;Carew NT;Cantu-Medellin N;Wood KC;Baty CJ;Schopfer FJ;Kelley EE;Gladwin MT;Martin E;Straub AC
可溶性鸟苷酸环化酶（sGC）血红素铁在其氧化状态（Fe3+）下对一氧化氮（NO）脱敏，并限制环鸟苷3 ',5 ' -单磷酸（cGMP）的产生，而cGMP是激活pkg依赖性信号和血管扩张所必需的。虽然已知活性氧可以氧化sGC血红素铁，但控制sGC血红素铁再循环到no敏感的还原状态的基本机制仍然知之甚少。氧化挑战研究表明，血管平滑肌细胞具有内在的能力来减少氧化的sGC血红素铁，并在细胞色素b5还原酶3 (Cyb5R3)（也称为高铁血红蛋白还原酶）和氧化的sGC之间形成蛋白-蛋白复合物。VSMCs的基因敲低和药理抑制表明，Cyb5R3的表达和活性对no刺激的cGMP产生和血管舒张至关重要。通过生化、细胞和离体实验，我们发现Cyb5R3可以直接减少一氧化氮敏化所需的氧化sGC。总之，这些发现为NO-sGC-cGMP信号传导提供了新的见解，并揭示了Cyb5R3是VSMCs中第一个被发现的生理sGC血红素铁还原酶，作为cGMP产生和PKG依赖性信号传导的关键调节因子。
Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe3+), is desensitized to nitric oxide (NO) and limits cyclic guanosine 3′, 5′-monophosphate (cGMP) production needed for downstream activation of PKG-dependent signaling and blood vessel dilation. While reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO-sensitive, reduced state, remain poorly understood. Oxidant challenge studies show vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein-protein complexes between cytochrome b5 reductase 3 (Cyb5R3), also known as methemoglobin reductase, and oxidized sGC. Genetic knockdown and pharmacological inhibition in VSMCs reveal Cyb5R3 expression and activity is critical for NO-stimulated cGMP production and vasodilation. Mechanistically, we show Cyb5R3 directly reduces oxidized sGC required for NO sensitization as assessed by biochemical, cellular, and ex vivo assays. Together, these findings identify new insights into NO-sGC-cGMP signaling and reveal Cyb5R3 as the first identified physiological sGC heme iron reductase in VSMCs, serving as a critical regulator of cGMP production and PKG dependent signaling.