Captopril Modulates Hypoxia-Inducible Factors and Erythropoietin Responses in a Murine Model of Total Body Irradiation
UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PHARMACOLOGY
Pagination or Media Count:
Objective. Our laboratory reported that the angiotensin converting enzyme inhibitor captopril improves erythroid recovery from total body irradiation TBI in mice when administered after irradiation. However, captopril administered before TBI attenuates erythroid recovery. Here we investigate captopril and radiation regulation of erythropoietin EPO and thrombopoietin TPO, key effectors of erythroid progenitor proliferation and differentiation. Materials and Methods. C57BL6 mice, nonirradiated or exposed to 7.5 Gy TBI 60Co, 0.6 Gymin were untreated or administered captopril. Plasma EPO and TPO levels were measured by enzyme-linked immunosorbent assay. Gene expression of EPO was determined by quantitative reverse transcription polymerase chain reaction. The hypoxia-inducible factors HIF-1a and -2a were measured by immunoblotting. Results. In nonirradiated mice, continuous captopril administration in the water transiently reduced reticulocytes and red blood cells after 7 and 10 days, respectively. EPO plasma levels and gene expression were reduced below detectable limits after 2 days of captopril treatment, but recovered within 7 days. HIF-1a and HIF-2a were activated preceding reticulocyte and red blood cell recovery. TBI, which ablates early and late-stage erythroid progenitors, activated both HIFs and increased EPO and TPO. Captopril treatment postirradiation suppressed radiation-induced HIF activation and EPO expression. In contrast, captopril administration for 7 days before TBI resulted in earlier EPO induction and activation. Captopril treatment lowered TPO levels in nonirradiated mice, but had minimal effects on radiation-induced TPO. Conclusions. In nonirradiated mice, captopril biphasically regulates EPO via HIF activation. TBI ablates erythroid progenitors, resulting in hypoxia, HIF activation, and increased EPO expression that are modulated by captopril treatment.
- Medicine and Medical Research