Molecular basis for hypoxic sensing and regulation of ventilatory responses

我们已经证明，缺乏血红素加氧酶-2（HO-2）的纯合子小鼠表现出迟钝的缺氧反应，而纯合子黑眼白色（bw）小鼠（小眼症相关转录因子（Mitf）的突变体）表现出增强的缺氧反应。上述结果提示HO-2和Mitf参与了缺氧性代偿反应。此外，我们还获得了以下结果：1 HO-2缺陷小鼠表现出轻度低氧血症和肺静脉心肌增厚，其中HO-1，一种血红素加氧酶的诱导型同工酶，过度表达。2在常压低氧7天小鼠肝脏HO-1和HO-2蛋白表达水平短暂下降，而HO-1和HO-2蛋白在缺氧28天时在心脏中增加。3使用9个近交系小鼠品系，我们用全身体积描记法测量了未麻醉小鼠对缺氧（10%O_2）和高碳酸血症（10%CO_2）的呼吸反应。基础呼吸变量和缺氧呼吸反应不同的菌株，但高碳酸血症呼吸反应没有差异。SWR/J小鼠的缺氧反应最低。因此，遗传因素可能会影响缺氧的缓解反应。4使用cDNA微阵列，我们已经确定了脂质运载蛋白型前列腺素D合成酶（L-PGDS），其mRNA在纯合bw小鼠皮肤中检测不到。L-PGDS是一种新发现的黑素细胞标志物。MITF可能通过激活黑素细胞中的L-PGDS基因来调节前列腺素D_2的产生。5低氧（1%O_2）孵育48 h后，降低了几种人类细胞系（如YN-1人类红白血病和HepG 2人类肝癌）中HO-1和HO-2蛋白的表达水平。缺氧48 h后，YN-1和HepG 2细胞血红素含量明显增加。

We have shown that homozygous mice lacking heme oxygenase-2 (HO-2) show blunted hypoxic ventilatory response and homozygous black-eyed white (bw) mice, a mutant in microphthalmia-associated transcription factor (Mitf), show augmented hypoxic ventilatory response. These results suggest the involvement of HO-2 and Mitf in hypoxic ventilatory response. Moreover, we have obtained the following results.1 HO-2 deficient mice exhibit mild hypxoemia and thickening of the pulmonary venous myocardium, in which HO-1,an inducible isozyme of heme oxygenase, is over-expressed.2 The expression levels of HO-1 and HO-2 proteins were transiently decreased in the mouse liver at 7 days of normobaric hypoxia, whereas HO-1 and HO-2 proteins were increased in the heart at 28 days of hypoxia.3 Using nine inbred mouse strains, we measured ventilatory responses to hypoxia (10% O_2) and hypercapnia (10% CO_2) of unanesthetized mice by whole body plethysmography. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the lowest in SWR/J mice. Thus, genetic factors may have influenced the hypoxic ventilatory response.4 Using cDNA microarrays, we have identified lipocalin-type prostaglandin D synthase (L-PGDS), whose mRNA is undetectable in the homozygous bw mouse skin. L-PGDS represents a newly identified melanocyte marker. MITF may modulate the production of prostaglandin D_2 by activating the L-PGDS gene in melanocytes.5 Hypoxia (1% O_2) reduces the expression levels of HO-1 and HO-2 protein in several human cell lines, such as YN-1 human erythroleukemia and HepG2 human hepatoma, after 48 h of incubation. Moreover, heme contents were increased in YN-1 and HepG2 cells after 48-h incubation under hypoxia.