Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation

Abstract

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 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. Methods C57BL/6 mice were either sham irradiated or were 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 of 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 Linprogenitor 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.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…In normal mice, ACE inhibition shows a biphasic modulation of bone marrow progenitor proliferation. Short-term ACE inhibition (2 days) suppressed the G0 to G1 transition of Lin 2 cells (i.e., bone marrow progenitor cells) (Davis et al, 2010). This effect of short-term ACE inhibition reduces the potential shortterm injury to stem cells, and is what was seen in the irradiation experiments described earlier that resulted in enhanced stem-cell survival (Charrier et al, 2004).…”

“…This effect of short-term ACE inhibition reduces the potential shortterm injury to stem cells, and is what was seen in the irradiation experiments described earlier that resulted in enhanced stem-cell survival (Charrier et al, 2004). In contrast, longer-term treatment with ACE inhibitors (greater than 7 days) appeared to increase the proliferation of bone marrow progenitors (Davis et al, 2010). The paradoxical effects between acute versus chronic ACE inhibition imply that ACE regulates hematopoiesis through multiple peptides and/or pathways.…”

The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis

“…Short-term ACE inhibition (2 days) suppressed the G 0 to G 1 transition. 77 This effect of short-term ACE inhibition is what was seen in the irradiation experiments described above that resulted in enhanced survival of stem cells. 76 In contrast, longer-term treatment with ACE inhibitors (greater than 7 days) appears to increase proliferative progenitors compared to untreated control mice.…”

“…76 In contrast, longer-term treatment with ACE inhibitors (greater than 7 days) appears to increase proliferative progenitors compared to untreated control mice. 77 The paradoxical effects between acute vs. chronic ACE activity deprivation implies that ACE regulates hematopoiesis through multiple peptides or pathways. Further complicating the story is examination of HSC populations in ACE-KO that ACE + CD34 +/-CD45 -are the markers for hemangioblast because such cells produced progenitors for both endothelium and lympho-hematopoietic stem cells.…”

Effects of ferulic acid on hematopoietic cell recovery in whole-body gamma irradiated mice

“…Hematopoietic progenitor cell colony-forming assay was investigated as described previously (Davis et al 2010). Three mice in each group were sacrificed at the seventh day after irradiation and bone marrow from femur were collected and mixed.…”