Studies on expression of bioactive substances under hypoxia and relation to diseases

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We studied novel peptides, such as adrenomedullin, and heme Oxygenase, particularly changes of their expression under hypoxia.1.Adrenomedullin expression was induced by hypoxia (1% O_2) in various types of cultured cells. Expression of RAMP2,a component of adrenomedullin receptor, was decreased under hypoxia in IMR-32 neuroblastoma cells, suggesting an adaptation mechanism against hypoxia.2.Urocortin and urocortin III were expressed not only in the brain, but also in the heart. These stress hormones may act as local regulators in the heart under stresses such as ischemia and hypoxia.3.Plasma levels of orexin-A were decreased in parallel with the severity in patients with obstructive sleep apnea hypopnea syndrome. Orexin-A in the hypothalamus may be related to the brain hypoxia due to apnea and hypopnea.4.Plasma levels of urotensin-II, a potent vasoactive peptide, were increased in patients with chronic renal failure or diabetes mellitus. Urotensin-II is expressed in various types of tumors and stimulates cell proliferation.5.Expression of heme oxygenase-1 had been thought to be induced by hypoxia. We found, however that expression of heme oxygenase-1 is decreased under hypoxia in certain types of human cells. Bach1 is a transcriptional factor that acts on MARE and inhibits the transcription. Bach1 was induced by hypoxia, and may act on the MARE located in the 5' upstream region (-4.5kb--4.0kb) of human heme oxygenase-1 gene. On the other hand, Heme oxygenase-1 was induced by hypoxia in other types of human cells, independently of MARE and Bach1.