Takabuchi Satoshi, Hirota Kiichi, Nishi Kenichiro, Oda Seiko, Oda Tomoyuki, Shingu Koh, Takabayashi Arimichi, Adachi Takehiko, Semenza Gregg L, Fukuda Kazuhiko
Department of Anesthesia, The Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan.
Biochem Biophys Res Commun. 2004 Nov 5;324(1):417-23. doi: 10.1016/j.bbrc.2004.09.064.
Adaptation to hypoxia and maintenance of O(2) homeostasis involve a wide range of responses that occur at different organizational levels in the body. One of the most important transcription factors that activate the expression of O(2)-regulated genes is hypoxia-inducible factor 1 (HIF-1). Nitric oxide (NO) mediates a variety of biological effects including relaxation of blood vessels and cytotoxicity of activated macrophages. We investigated the effect of the clinically used nitrates nitroglycerin (NTG), isosorbide dinitrate (ISDN), and sodium nitroprusside (SNP) on HIF-1-mediated transcriptional responses to hypoxia. We demonstrate that among the three nitrates, only SNP inhibits HIF-1 activation in response to hypoxia. In contrast, NTG or ISDN does not affect HIF-1 activity. SNP inhibits the accumulation of HIF-1alpha, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1alpha via a mechanism that is not dependent on either NO or soluble guanylate cyclase.
对缺氧的适应和氧气稳态的维持涉及身体不同组织水平上发生的广泛反应。激活氧调节基因表达的最重要转录因子之一是缺氧诱导因子1（HIF-1）。一氧化氮（NO）介导多种生物学效应，包括血管舒张和活化巨噬细胞的细胞毒性。我们研究了临床使用的硝酸盐硝酸甘油（NTG）、异山梨醇二硝酸酯（ISDN）和硝普钠（SNP）对HIF-1介导的缺氧转录反应的影响。我们证明，在这三种硝酸盐中，只有SNP抑制对缺氧的HIF-1激活。相比之下，NTG或ISDN不影响HIF-1活性。SNP通过一种不依赖于NO或可溶性鸟苷酸环化酶的机制抑制HIF-1α（HIF-1的调节亚基）的积累以及HIF-1α的转录激活。
