The inhibitory effect of sodium nitroprusside on HIF-1 activation is not dependent on nitric oxide- soluble guanylyl cyclase pathway


Satoshi Takabuchi, Kiichi Hirota, Kenichiro Nishi a, Seiko Oda, Tomoyuki Oda, Koh Shingu, Arimichi Takabayashi, Takehiko Adachi, Gregg L. Semenza and Kazuhiko Fukuda

Biochemical and Biophysical Research Communications, vol. 324 p417-23

Abstract

Adaptation to hypoxia and maintenance of O2 homeostasis involve a wide range of responses that occur at different organizational levels in the body. One of the most important transcription factors that activates the expression of O2-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-1α, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1α via a mechanism that is not dependent on either NO or soluble guanylate cyclase.


Key Words: nitroglycerin, isosorbide dinitrate, sodium nitroprusside, nitric oxide, hypoxia, hypoxia-inducible factor 1, hydroxylase, von Hippel-Lindau

Posted: 土 - 9月 11, 2004 at 12:46 午後          

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