title: Captopril modulates hypoxia-inducible factors and erythropoietin responses in a murine model of total body irradiation.
abstract: 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.
  
  
  METHODS
  C57BL/6 mice, nonirradiated or exposed to 7.5 Gy TBI ((60)Co, 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.
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20892, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Barshishat-Kupper
authors.forename: Ognoon
authors.initials: O
authors.lastname: Mungunsukh
authors.forename: Ashlee J
authors.initials: AJ
authors.lastname: Tipton
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McCart
authors.forename: Ronald A M
authors.initials: RA
authors.lastname: Panganiban
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
authors.forename: Michael R
authors.initials: MR
authors.lastname: Landauer
authors.forename: Regina M
authors.initials: RM
authors.lastname: Day
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D004921:Erythropoietin / Q000096:biosynthesis*; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D013926:Thrombopoietin / Q000096:biosynthesis; D013997:Time Factors; D014916:Whole-Body Irradiation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D002216:Captopril; D004921:Erythropoietin; D013926:Thrombopoietin