TY - JOUR
T1 - Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation
AU - Davis, Thomas A.
AU - Landauer, Michael R.
AU - Mog, Steven R.
AU - Barshishat-Kupper, Michal
AU - Zins, Stephen R.
AU - Amare, Mihret F.
AU - Day, Regina M.
N1 - Funding Information:
We thank Harley Clinton for hematology support, and Asline Khnachar for histology support, and Patricia Lissner for editorial assistance on an earlier version of this manuscript. 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 defines 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 (Bethesda, MD, USA), the Armed Forces Radiobiology Research Institute (Bethesda, MD, USA), Department of the Navy (Washington, DC, USA), Department of Defense (Washington, DC, USA) or the U.S. Federal Government (Washington, DC, USA). This work was supported by: National Institutes of Health (Bethesda, MD, USA) grant HL73929 and a Uniformed Services University of the Health Sciences Research grant (R.M.D.), Defense Threat Reduction Agency (Fort Belvoir, VA, USA) grant H.10025_07_R (R.M.D. and M.R.L.), and Navy Medical Research Center (Silver Spring, MD, USA) In-House Laboratory Independent Research grant 601152N.05580.2130.A0704 (T.A.D.).
PY - 2010/4
Y1 - 2010/4
N2 - Objective: Angiotensin II (Ang II), a potent vasoconstrictor, affects the growth and development of hematopoietic cells. Mixed findings have been reported for the effects of angiotensin-converting enzyme (ACE) inhibitors on radiation-induced injury to the hematopoietic system. We investigated the consequences of different regimens of the ACE inhibitor captopril on radiation-induced hematopoietic injury. Materials and Methods: C57BL/6 mice were either sham-irradiated or exposed to 60Co total body irradiation (0.6 Gy/min). Captopril was provided in the water for different time periods relative to irradiation. Results: In untreated mice, the survival rate from 7.5 Gy was 50% at 30 days postirradiation. Captopril treatment for 7 days prior to irradiation resulted in radiosensitization with 100% lethality and a rapid decline in mature blood cells. In contrast, captopril treatment beginning 1 hour postirradiation and continuing for 30 days resulted in 100% survival, with improved recovery of mature blood cells and multilineage hematopoietic progenitors. In nonirradiated control mice, captopril biphasically modulated Lin- marrow progenitor cell cycling. After 2 days, captopril suppressed G0-G1 transition and a greater number of cells entered a quiescent state. However, after 7 days of captopril treatment Lin- progenitor cell cycling increased compared to untreated control mice. Conclusion: These findings suggest that ACE inhibition affects hematopoietic recovery following radiation by modulating the hematopoietic progenitor cell cycle. The timing of captopril treatment relative to radiation exposure differentially affects the viability and repopulation capacity of spared hematopoietic stem cells and, therefore, can result in either radiation protection or radiation sensitization.
AB - Objective: Angiotensin II (Ang II), a potent vasoconstrictor, affects the growth and development of hematopoietic cells. Mixed findings have been reported for the effects of angiotensin-converting enzyme (ACE) inhibitors on radiation-induced injury to the hematopoietic system. We investigated the consequences of different regimens of the ACE inhibitor captopril on radiation-induced hematopoietic injury. Materials and Methods: C57BL/6 mice were either sham-irradiated or exposed to 60Co total body irradiation (0.6 Gy/min). Captopril was provided in the water for different time periods relative to irradiation. Results: In untreated mice, the survival rate from 7.5 Gy was 50% at 30 days postirradiation. Captopril treatment for 7 days prior to irradiation resulted in radiosensitization with 100% lethality and a rapid decline in mature blood cells. In contrast, captopril treatment beginning 1 hour postirradiation and continuing for 30 days resulted in 100% survival, with improved recovery of mature blood cells and multilineage hematopoietic progenitors. In nonirradiated control mice, captopril biphasically modulated Lin- marrow progenitor cell cycling. After 2 days, captopril suppressed G0-G1 transition and a greater number of cells entered a quiescent state. However, after 7 days of captopril treatment Lin- progenitor cell cycling increased compared to untreated control mice. Conclusion: These findings suggest that ACE inhibition affects hematopoietic recovery following radiation by modulating the hematopoietic progenitor cell cycle. The timing of captopril treatment relative to radiation exposure differentially affects the viability and repopulation capacity of spared hematopoietic stem cells and, therefore, can result in either radiation protection or radiation sensitization.
UR - http://www.scopus.com/inward/record.url?scp=77950791504&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2010.01.004
DO - 10.1016/j.exphem.2010.01.004
M3 - Article
C2 - 20116413
AN - SCOPUS:77950791504
SN - 0301-472X
VL - 38
SP - 270
EP - 281
JO - Experimental Hematology
JF - Experimental Hematology
IS - 4
ER -