Accumulated evidence indicates that hypoxia activates collagen synthesis in tissues. To explore the molecular mechanism of activation, we screened genes that are up-regulated or down-regulated by hypoxia. Fibroblasts isolated from fetal rat lung were cultured under hypoxia. Differential display technique showed that the mRNA level of prolyl 4-hydroxylase (PH) ␣(I), an active subunit that catalyzes the oxygen-dependent hydroxylation of proline residue in procollagen, increased 2-3-fold after an 8-h exposure to hypoxia. This elevated level was maintained over 40 h and returned to the basal level after reoxygenation. The transcription rate, protein level, and hydroxyproline content (an indicator of the prolyl hydroxylation) were all elevated by hypoxic culture. Analysis of the promotor region of PH␣(I) gene indicated that a motif similar to hypoxia-responsive element (HRE) of hypoxia-inducible genes such as erythropoietin, was identified within a 120-base pair sequence upstream of the transcription start site. Luciferase reporter assay and mutational analysis showed that a site similar to the HRE in this motif is functionally essential to hypoxic response. Electrophoretic mobility shift assay revealed that hypoxia-inducible factor-1 was stimulated and bound to the PH␣(I) HRE upon hypoxic challenge. Our results indicate that PH␣(I), an essential enzyme for collagen synthesis, is a target gene for hypoxia-inducible factor-1.Restricted oxygen availability is a feature of many physiologic and pathologic conditions, including high altitude residence, fetal development in the uterus, pulmonary fibrosis, wounded tissue, and neoplasm (1). Systemic and cellular responses to reduced oxygen tension (hypoxia) are initiated by activation and/or inactivation of gene expression. Hypoxia-inducible factor-1 (HIF-1), 1 which was originally found to be a critical mediator for the inducible expression of the erythropoietin (Epo) gene by hypoxia (2), is a heterodimer composed of HIF-1␣ and arylhydrocarbon receptor nuclear translocator (ARNT). HIF-1␣ and ARNT retain a basic helix-loop-helix domain and a Per-ARNT/aryl hydrocarbon receptor Sim domain in their N termini (2). Hypoxia induces stabilization of HIF-1␣ (3), heterodimerization of HIF-1␣ and ARNT (4), and the binding of the heterodimer to the hypoxia-responsive element (HRE) in the regulatory region of the target genes with the transcriptional coactivator p300/CREB-binding protein (5). Although posttranscriptional mechanisms may contribute to the induction of hypoxia-sensitive genes, activation of the HIF-1 complex is an important step leading to hypoxia-mediated induction of glycolytic enzymes (6 -9), Epo (2), vascular endothelial growth factor (10), and tyrosine hydroxylase (11).In the remodeling of the small muscular pulmonary artery observed in hypoxia-induced pulmonary hypertension, type I collagen is actively synthesized and accumulated in the media and the adventitia of the artery (12). Recent studies have revealed that in vivo exposure of rats to hypoxia increases prolyl ...
The vanadium(V) ion, which is described as VV herein, could hardly oxidize the iodide ion to iodine at pH ≥ 2.8; however, the oxidation reaction occurred catalytically upon adding traces of copper(II) ion. When a copper(II) solution of 10−8—10−5 M (M = mol dm−3) was mixed with an iodide solution, after a rapid formation of iodine, the iodine concentration remained constant. After such iodine formation had occurred, if a VV solution was added into the reacting mixture, the iodine began to form again in accordance with a rate law of 2(d[I2]/dt) = −d[VV]/dt = k[CuI][VV], in which [CuI] is a steady-states’ concentration in a chain cycle CuI+/CuI. The reaction rate was independent of the time to add the VV ion, and the formation of iodine I2 (or triiodide ion I3−) stopped at the time when all of the VV was consumed, indicating the stoichiometry to be 2I− + 2VV → I2 + 2VIV. The initial rate (Vi) after VV addition was proportional to the concentrations of not only the added VV over the range 10−6—10−5 M, but also the added copper(II) ion. Although a self-inhibiting effect did not appear over the pH range 2.8—3.6, it occurred at pH > 3.6. It was found that such a retarding effect was caused by the vanadium(IV) ion (denoted as VIV herein), which was the reduced product of VV; the VIV inhibiting effect was extremely dependent on the pH in the reacting solution. The mechanisms for the retardation reaction as well as iodine formation are discussed in terms of accounting for the obtained results.
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