Induction of heme oxygenase-1 by hypoxia and free radicals in human dermal fibroblasts

被引:98
作者
Panchenko, MV [1 ]
Farber, HW
Korn, JH
机构
[1] Boston Univ, Sch Med, Ctr Arthritis, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Rheumatol Sect, Boston, MA 02118 USA
[3] Boston Univ, Sch Med, Ctr Pulm, Dept Med, Boston, MA 02118 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2000年 / 278卷 / 01期
关键词
stress response; messenger ribonucleic acid stability; iron depletion; scleroderma;
D O I
10.1152/ajpcell.2000.278.1.C92
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme catabolism and presumably is involved in cellular iron homeostasis. It is induced by a variety of cellular stresses, including oxygen deprivation and free radical-mediated stress. We examined induction of HO-1 mRNA in shin fibroblasts and investigated the mechanism by which it occurs. Hypoxia did not appear to act via induction of oxygen free radicals: induction of HO-1 was not sensitive to the free radical scavenger GSH or other antioxidants. Moreover, hypoxia did not increase steady-state levels of free radicals generated by fibroblasts. In contrast, HO-1 induction by the oxidants, H2O2 and carbonyl cyanide m-chlorophenylhydrazone (CCCP) was significantly attenuated in the presence of free radical scavengers. This correlated with increased levels of free radical production in fibroblasts treated with these oxidants. Iron depletion by desferrioxamine mesylate, a specific iron complexon, completely inhibited hypoxic stimulation of HO-1 but did not attenuate the effect of H2O2 and CCCP on HO-1 mRNA. Addition of Fe2+, Fe3+, or holo-transferrin to fibroblasts increased levels of HO-1 mRNA. Treatment of cells with hypoxia, but not H2O2 or an exogenous source of iron, significantly increased the half-life of HO-1 mRNA. The data suggest hypoxia regulates HO-1 gene expression by aspecific posttranscriptional mechanism: stabilization of mRNA. Hypoxia has previously been shown to increase fibroblast collagen synthesis and is thought to play a role in pathogenesis of systemic sclerosis (SSc). Skin fibroblasts isolated from patients with SSc demonstrated significantly stronger induction of HO-1 by hypoxia than did fibroblasts from normal controls. We hypothesize that exposure of SSc fibroblasts to hypoxic conditions leads to in vivo selective proliferation of cells that adapt to hypoxia.
引用
收藏
页码:C92 / C101
页数:10
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