Endothelial alpha globin is a nitrite reductase.
Endothelial alpha globin is a nitrite reductase.
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DOI：
10.1038/s41467-022-34154-3
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发表时间：
2022-10-27
影响因子：
16.6
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中科院分区：
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抵抗动脉血管扩张对缺氧的反应是匹配组织氧气和需求的必要条件。缺氧时，红细胞血红蛋白四聚体通过亚硝酸盐还原产生一氧化氮。我们假设内皮中表达的血红蛋白α亚基也促进了平滑肌近端亚硝酸盐的还原。在这里，我们创建了两个小鼠品系来测试这一点：内皮特异性α -珠蛋白敲除（EC Hba1Δ/Δ）和α -珠蛋白等位基因突变以阻止α -珠蛋白与内皮一氧化氮合酶的抑制相互作用（Hba1WT/ Δ36-39）。在缺氧条件下，EC Hba1Δ/Δ小鼠的运动能力和细胞内亚硝酸盐消耗显著降低，而Hba1WT/ Δ36-39小鼠则没有这种影响。缺氧诱导的血管舒张在EC Hba1Δ/Δ小鼠的动脉中显著降低，但在Hba1WT/ Δ36-39小鼠中没有。缺氧也不会降低EC Hba1Δ/Δ小鼠的血压。我们得出结论，抵抗动脉内皮中α -珠蛋白的存在作为亚硝酸盐还原酶在缺氧反应中提供局部一氧化氮。在哺乳动物中，缺氧导致小动脉扩张以增加代谢需求。Keller等人利用新型转基因小鼠表明，内皮中的α血红蛋白可以调节缺氧介导的扩张，而过去人们认为α血红蛋白只存在于红细胞中。
Resistance artery vasodilation in response to hypoxia is essential for matching tissue oxygen and demand. In hypoxia, erythrocytic hemoglobin tetramers produce nitric oxide through nitrite reduction. We hypothesized that the alpha subunit of hemoglobin expressed in endothelium also facilitates nitrite reduction proximal to smooth muscle. Here, we create two mouse strains to test this: an endothelial-specific alpha globin knockout (EC Hba1Δ/Δ) and another with an alpha globin allele mutated to prevent alpha globin’s inhibitory interaction with endothelial nitric oxide synthase (Hba1WT/Δ36–39). The EC Hba1Δ/Δ mice had significantly decreased exercise capacity and intracellular nitrite consumption in hypoxic conditions, an effect absent in Hba1WT/Δ36–39 mice. Hypoxia-induced vasodilation is significantly decreased in arteries from EC Hba1Δ/Δ, but not Hba1WT/Δ36–39 mice. Hypoxia also does not lower blood pressure in EC Hba1Δ/Δ mice. We conclude the presence of alpha globin in resistance artery endothelium acts as a nitrite reductase providing local nitric oxide in response to hypoxia. In mammals, hypoxia causes dilation of small arteries for increased metabolic demand. Keller et al used novel transgenic mice to show alpha hemoglobin in endothelium, once thought only in red blood cells, can regulate hypoxic-mediated dilation.
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