Abstract
AbstractAngiotensin I–converting enzyme (ACE) inhibitors can affect hematopoiesis by several mechanisms including inhibition of angiotensin II formation and increasing plasma concentrations of AcSDKP (acetyl-N-Ser-Asp-Lys-Pro), an ACE substrate and a negative regulator of hematopoiesis. We tested whether ACE inhibition could decrease the hematopoietic toxicity of lethal or sublethal irradiation protocols. In all cases, short treatment with the ACE inhibitor perindopril protected against irradiation-induced death. ACE inhibition accelerated hematopoietic recovery and led to a significant increase in platelet and red cell counts. Pretreatment with perindopril increased bone marrow cellularity and the number of hematopoietic progenitors (granulocyte macrophage colony-forming unit [CFU-GM], erythroid burst-forming unit [BFU-E], and megakaryocyte colony-forming unit [CFU-MK]) from day 7 to 28 after irradiation. Perindopril also increased the number of hematopoietic stem cells with at least a short-term reconstitutive activity in animals that recovered from irradiation. To determine the mechanism of action involved, we evaluated the effects of increasing AcSDKP plasma concentrations and of an angiotensin II type 1 (AT1) receptor antagonist (telmisartan) on radioprotection. We found that the AT1-receptor antagonism mediated similar radioprotection as the ACE inhibitor. These results suggest that ACE inhibitors and AT1-receptor antagonists could be used to decrease the hematopoietic toxicity of irradiation.
Highlights
Introduction led to a significant increase in platelet and red cell counts
angiotensin I–converting enzyme (ACE) inhibitors inhibit the formation of angiotensin II and prevent the degradation of AcSDKP increasing its concentration in plasma and urine.[20,21]
To determine whether ACE inhibitors can prevent myelotoxicity, we evaluated the radioprotective effect of an ACE inhibitor, perindopril, on survival and on bone marrow hematopoiesis in a mouse model after lethal and sublethal doses of irradiation
Summary
Introduction led to a significant increase in platelet and red cell counts. Pretreatment with perindopril increased bone marrow cellularity and the number of hematopoietic progenitors (granulocyte macrophage colony-forming unit [CFU-GM], erythroid burst-forming unit [BFU-E], and megakaryocyte colony-forming unit [CFU-MK]) from day 7 to 28 after irradiation. The renin-angiotensin system is an important determinant of vascular and fluid homeostasis as well as blood pressure regulation.[16] In addition, it regulates cellular growth in a variety of tissues through its principal effector, angiotensin II, and its 2 receptors, AT1 and AT2.17 ACE is a tissue-bound enzyme with 2 catalytic domains. It converts angiotensin I into angiotensin II and can cleave other peptides such as bradykinin and AcSDKP.[18] AcSDKP is almost exclusively degraded by the N-terminal domain of ACE,[15] whereas the other substrates are almost cleaved by the 2. Angiotensin II receptors (type AT1) have been detected on both erythroid and CD34ϩ cells.[22,23]
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