Ionizing radiation induces BH4 deficiency by downregulating intestinal
GTP-cyclohydrolase 1, a target for preventing and treating radiation
enteritis
Abstract
BACKGROUND AND PURPOSE Radiation enteritis (RE) is a common side effect
after radiotherapy for abdominal cancer. RE pathogenesis is complicated,
with no prevention or drug treatments. Intestinal ischemia is a key
factor in enteritis occurrence and development. Deficiency of
tetrahydrobiopterin (BH4) produced by GTP-cyclohydrolase 1 (Gch1) is
important in ischemic diseases of endothelial dysfunction. The influence
of ionizing radiation (IR) on intestinal ischemia is unknown. This study
examined the effects of IR on intestinal perfusion, vasodilation, and
Gch1/BH4. EXPERIMENTAL APPROACH BH4 levels were analysed by HPLC in
human plasma and rats after radiotherapy. Intestinal blood perfusion was
measured by laser Doppler flow imaging. Vascular ring tests determined
diastolic functions of rat mesenteric arteries. Gene, protein, and
immunohistochemical staining experiments and inhibitor interventions
were used to investigate Gch1 and endothelial NOS (eNOS) in rat
mesenteric arteries and endothelial cells. KEY RESULTS IR decreased BH4
levels in patient and rat plasma after radiotherapy and decreased
intestinal blood perfusion in rats. The degree of change in intestinal
ischemia was consistent with intestinal villus injury. Gch1 mRNA and
protein levels and NO production significantly decreased, while eNOS
uncoupling in arterial and vascular endothelial cell strongly increased.
BH4 supplementation improved eNOS uncoupling and NO levels in vascular
endothelia after IR. CONCLUSIONS AND IMPLICATIONS Downregulation of Gch1
in intestinal blood vessels after IR is an important target in RE. BH4
supplementation may prevent intestinal ischemia and improve vascular
endothelial function after IR. This result has clinical significance for
prevention and treatment of RE.