S-Nitrosoglutathione (SNOG) Accumulates Hypoxia Inducible Factor-1α in Main Pulmonary Artery Endothelial Cells but not in Micro Pulmonary Vessel Endothelial Cells
Adequate cellular oxygen tension is essential for maintaining a variety of physiological process. Disorder of oxygen delivery eventually leads to the cell dysfunction. Therefore, sensing mechanism of cellular hypoxia is critical. Under hypoxic condition, a lot of protein is induced in mammalian cells for preventing hypoxic stress. Hypoxia inducible factor-1 (HIF-1) is a transcription factor protein that thought to be a one of the key molecule as gatekeeper of cellular hypoxia. HIF-1 regulates the expression of series of genes involved in angiogenesis, oxygen transport and glucose metabolism (1, 2). Most of these gene products utilize for the maintaining O2 homeostasis. HIF-1 is composed of two subunit called HIF-1α and HIF1β (3). In normoxic and hypoxic condition, HIF-1α and HIF1β mRNA are constitutively expressed (4). With regard to the protein level, HIF-1α is hydroxylated at Pro402 and Pro564 by the enzyme designated prolyl hydroxylase domain containing protein (PHD) under normoxia (5, 6). Hydroxylated HIF-1α binds to the von Hippel Lindau protein (pVHL), which is the substrate for ubiquitin ligase complex (7). Therefore, HIF-1α is rapidly degraded under normoxia by the ubiquitin-protease pathway (8, 9, 10). When cells are exposed to hypoxia, HIF-1α protein escapes from this degradation system. Subsequently, accumulated HIF-1α protein translocates to the nucleus, and dimerizes with HIF-1β 11). This heterodimeric protein binds to hypoxia-responsive element (HRE) and induces transcription of downstream genes (12). Thus, transcriptional activity of HIF-1 is primarily dependent on the HIF-1α expression.
KeywordsNitric Oxide Nitric Oxide Primary Pulmonary Hypertension Vascular Endothelial Growth Factor Gene Pulmonary Artery Endothelial Cell
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