Accelerated hematopoietic recovery with angiotensin-(1–7) after total body radiation

Abstract

Purpose: Angiotensin (1–7) [A(1–7)] is a component of the renin angiotensin system (RAS) that stimulates hematopoietic recovery after myelosuppression. In a Phase I/IIa clinical trial, thrombocytopenia after chemotherapy was reduced by A(1–7). In this study, the ability of A(1–7) to improve recovery after total body irradiation (TBI) is shown with specific attention to radiation-induced hematopoietic injury. Materials and methods: Mice were exposed to TBI (doses of 2–7 Gray [Gy]) of cesium 137 gamma rays, followed by treatment with A(1–7), typical doses were 100–1000 μg/kg given once or once daily for a specified number of days depending on the study. Animals are injected subcutaneously via the nape of the neck with 0.1 ml drug in saline. The recovery of blood and bone marrow cells was determined. Effects of TBI and A(1–7) on survival and bleeding time was also evaluated. Results: Daily administration of A(1–7) after radiation exposure improved survival (from 60% to 92–97%) and reduced bleeding time at day 30 after TBI. Further, A(1–7) increased early mixed progenitors (3- to 5-fold), megakaryocyte (2- to 3-fold), myeloid (3- to 6-fold) and erythroid (2- to 5-fold) progenitors in the bone marrow and reduced radiation-induced thrombocytopenia (RIT) (up to 2-fold). Reduction in the number of treatments to 3 per week also improved bone marrow recovery and reduced RIT. As emergency responder and healthcare systems in case of nuclear accident or/and terrorist attack may be overwhelmed, the consequence of delayed initiation of treatment was ascertained. Treatment with A(1–7) can be delayed up to 5 days and still be effective in the reduction of RIT or acceleration of bone marrow recovery. Conclusions: The data presented in this paper indicate that A(1–7) reduces the consequences of critical radiation exposure and can be initiated well after initial exposure with maximal effects on early responding hematopoietic progenitors when treatment is initiated 2 days after exposure and 5 days after exposure for the later responding progenitors and reduced thrombocytopenia. There was some effect of A(1–7) even when given days after radiation exposure.

Angiotensin 1 – 7 stimulation of platelet recovery

“…As previously demonstrated in models of chemotherapy, A(1 --7) treatment also increased the concentration of megakaryocyte progenitors (two-to threefold increase) in the bone marrow and reduced RIT (twofold reduction) (Figure 2). Results were improved when A(1 --7) was delayed greater than 24 h post-TBI, which is consistent with the hypothesis that immature progenitor cells are more sensitive to the proliferative effects of A(1 --7) than mature cells [31].…”

“…Every known component of the RAS is contained within bone marrow cells, including mRNA for angiotensinogen, renin, ACE, angiotensin II receptors type 1 and 2 (AT 1 and AT 2 , respectively), Mas, and ACE 2 [25][26][27]. Extensive evidence indicates a significant role for the RAS in regulation of hematopoiesis and the development of hematopoietic progenitor cells [28][29][30][31][32][33]. Additionally, alterations in the RAS have been implicated in a variety of human hematopoietic diseases including myelodysplastic syndrome [34] and anemia [35,36].…”

“…and A(1 --7) stimulation of hematopoiesis is hypothesized to be through the Mas receptor. The ability of A(1 --7) to accelerate hematopoietic recovery was blocked by administration of Mas, but not AT 1 or AT 2 antagonists [31,40]. Although expression of Mas in normal bone marrow is low, A(1 --7) increases the number of early and late progenitor cells that express Mas.…”

“…Optimization of the appropriate dosing regimen has been performed in murine models of total body irradiation (TBI), with dosing initiated up to 10 days post-irradiation [31,45]. Studies showed that daily dosing with A(1 --7) resulted in a dose-dependent improvement in bone marrow progenitors and circulating formed elements, including platelets, and that the effects and higher doses were optimal when treatment was started at least 48 h after irradiation [31].…”

“…Studies showed that daily dosing with A(1 --7) resulted in a dose-dependent improvement in bone marrow progenitors and circulating formed elements, including platelets, and that the effects and higher doses were optimal when treatment was started at least 48 h after irradiation [31]. Overall, A(1 --7) significantly improved platelet levels compared to saline-treated controls, improved survival (from 60 to > 90%) and reduced bleeding time 30 days after TBI.…”