Hypoxia, or a low concentration of O2, is encountered in humans undertaking activities such as mountain climbing and scuba diving and is important pathophysiologically as a limiting factor in
tumor growth. Although data on the interplay between
hypoxia and
gastrins are limited,
gastrin expression is upregulated by
hypoxia in
gastrointestinal cancer cell lines, and
gastrins counterbalance
hypoxia by stimulating angiogenesis in vitro and in vivo. The aim of this study was to determine if higher concentrations of the
gastrin precursor
progastrin are protective against
hypoxia in vivo. hGAS mice, which overexpress
progastrin in the liver, and mice of the corresponding wild-type FVB/N strain were exposed to normoxia or
hypoxia.
Iron status was assessed by measurement of serum
iron parameters, real-time PCR for mRNAs encoding critical
iron regulatory proteins, and Perls'
stain and atomic absorption spectrometry for tissue
iron concentrations. FVB/N mice lost weight at a faster rate and had higher sickness scores than hGAS mice exposed to
hypoxia. Serum
iron levels were lower in hGAS than FVB/N mice and decreased further when the animals were exposed to
hypoxia. The concentration of
iron in the liver was strikingly lower in hGAS than FVB/N mice. We conclude that increased circulating concentrations of
progastrin provide a physiological advantage against systemic
hypoxia in mice, possibly by increasing the availability of
iron stores. This is the first report of an association between
progastrin overexpression,
hypoxia, and
iron homeostasis.