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Ionizing radiation induces BH4 deficiency by downregulating intestinal GTP-cyclohydrolase 1, a target for preventing and treating radiation enteritis
  • Tao Yan
Tao Yan
Tangdu Hospital Fourth Military Medical University
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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.