TY - JOUR
T1 - Captopril modulates hypoxia-inducible factors and erythropoietin responses in a murine model of total body irradiation
AU - Barshishat-Kupper, Michal
AU - Mungunsukh, Ognoon
AU - Tipton, Ashlee J.
AU - McCart, Elizabeth A.
AU - Panganiban, Ronald A.M.
AU - Davis, Thomas A.
AU - Landauer, Michael R.
AU - Day, Regina M.
N1 - Funding Information:
We thank Young H. Lee for assistance with rodent handling. Some of the authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C §101 defined a U.S. Government work as a work prepared by a military service member or employees of the U.S. Government as part of that person’s official duties. The views in this article are those of the authors and do not necessarily reflect the views, official policy, or position of the Uniformed Services University of the Health Sciences, the Armed Forces Radiobiology Research Institute, Department of the Navy, Department of Defense or the U.S. Federal Government. This work was supported by National Institutes of Health grant HL73929 and a Uniformed Services University of the Health Sciences Research grant (R.M.D.), Defense Threat Reduction Agency grant H.10025_07_R (R.M.D. and M.R.L.), Naval Medical Research Center In-House Laboratory Independent Research Program grant 601152N.05580.2130.A0704 (T.A.D.).
PY - 2011/3
Y1 - 2011/3
N2 - 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: C57BL/6 mice, nonirradiated or exposed to 7.5 Gy TBI (60Co, 0.6 Gy/min) 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)-1α and -2α 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-1α and HIF-2α 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. These data suggest that short-term suppression of radiation-induced EPO immediately after TBI is favorable for erythroid recovery.
AB - 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: C57BL/6 mice, nonirradiated or exposed to 7.5 Gy TBI (60Co, 0.6 Gy/min) 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)-1α and -2α 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-1α and HIF-2α 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. These data suggest that short-term suppression of radiation-induced EPO immediately after TBI is favorable for erythroid recovery.
UR - http://www.scopus.com/inward/record.url?scp=79951936497&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2010.12.002
DO - 10.1016/j.exphem.2010.12.002
M3 - Article
C2 - 21146580
AN - SCOPUS:79951936497
SN - 0301-472X
VL - 39
SP - 293
EP - 304
JO - Experimental Hematology
JF - Experimental Hematology
IS - 3
ER -