Heme oxygenase in the brain

血红素加氧酶是血红素分解代谢中的一种重要酶，它能分解血红素释放一氧化碳、铁和胆绿素。至少存在两种类型的血红素加氧酶同工酶，即诱导型血红素加氧酶-1和结构性表达的血红素加氧酶-2。我们发现，NO供体如硝普钠可诱导人胶质母细胞瘤细胞(T98G和A172)、人宫颈癌细胞(HeLa)、黑色素瘤细胞(MeWo)和结肠癌细胞(DLD-1)表达血红素加氧酶-L。用DLD-1细胞进行瞬时转染实验表明，硝普钠诱导的血红素加氧酶-1是由位于人血红素加氧酶-1基因启动子区域的镉反应元件和AP-1介导的。此外，我们还发现人血红素加氧酶-1基因启动子区域(约-200b)的a(GT)n重复序列是高度多态的。另一方面，干扰素-γ显著抑制了T98G细胞中血红素加氧酶-1mRNA的表达，提示脑内存在一种对血红素加氧酶-L过度表达的调节系统。肾上腺髓质素是从嗜铬细胞瘤中分离出来的一种血管扩张多肽。虽然最初报道肾上腺髓质素在大脑中不存在，但我们发现肾上腺髓质素及其mRNA在人脑和脑垂体中高度表达。肾上腺髓质素由多种肿瘤产生，包括胶质母细胞瘤、脉络丛癌和结肠癌，提示肾上腺髓质素与肿瘤细胞的生长和增殖有关。血红素加氧酶-1已知是由低氧诱导的。我们发现，肾上腺髓质素也在低氧条件下被诱导。这种诱导可能是对低氧的防御反应，因为肾上腺髓质素具有血管扩张和支气管扩张作用。

Heme oxygenase is an essential enzyme in heme catabolism that cleaves heme to release carbon monoxide, iron and biliverdin. There are at least two types of heme oxygenase isozymes, inducible heme oxygenase-1 and constitutively expressed heme oxygenase-2. We have found that expression heme oxygenase-l is induced by NO donors, such as sodium nitroprusside, in variouskinds of cultured cells including human glioblastoma cells (T98G and A 172), human cervical cancer cells (HeLa), melanoma cells (MeWo) and colonic carcinoma cells (DLD)- 1). Transient transfection assays using DLD-1 cells revealed that heme oxygenase-1 induction by sodium nitroprusside was mediated by cadmium-responsive element and AP-1, which are located in the promoter region of human heme oxygenase-1 gene (about -4.0 kb). In addition, we showed that a(GT)n repeat in the human heme oxygenase-1 gene promotor region (about -200 b) is highly polymorphic. On the other hand, expression of heme oxygenase-1 mRNA was considerably suppressed by interferon-gamma in T98G cells, suggesting the presence of a regulatory system for heme oxygenase-l overexpression in the brain.Adrenomedullin is a vasodilator peptide isolated from pheochromocytoma. Although adrenomedullin was initially reported to be absent in the brain, we showed that adrenomedullinand its mRNA were highly expressed in the human brain and pituitary. Adrenomedullin is produced by various kinds of tumors including glioblastoma, choroid plexus carcinoma and colonic carcinoma, suggesting that adrenomedullin is related to the growth and proliferation of tumor cells. Heme oxygenase-1 is known to be induced by hypoxia. We showed that adrenomedullin was also induced by hypoxia. This induction may be a defense reaction agaist hypoxia, because adrenomedullin has vasodilator and bronchodilator actions.