Inhibition of angiotensin I–converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells

• Published in: Blood 2004-08, Vol.104 (4), p.978-985
• Main Authors: Charrier, Sabine, Michaud, Annie, Badaoui, Sabrina, Giroux, Sébastien, Ezan, Eric, Sainteny, Françoise, Corvol, Pierre, Vainchenker, William
• Format: Article
• Language: English
• Subjects: Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Animals; Biological and medical sciences; Biological effects of radiation; Blood Cells - drug effects; Blood Cells - radiation effects; Bone Marrow - drug effects; Bone Marrow - radiation effects; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Dose-Response Relationship, Radiation; Drug Evaluation, Preclinical; Female; Fundamental and applied biological sciences. Psychology; Hematopoiesis - drug effects; Hematopoiesis - radiation effects; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - radiation effects; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Peptidyl-Dipeptidase A; Perindopril - pharmacology; Perindopril - therapeutic use; Phosphinic Acids - pharmacology; Phosphinic Acids - therapeutic use; Radiation-Protective Agents - pharmacology; Radiation-Protective Agents - therapeutic use; Radioprotection; Survival Rate; Tissues, organs and organisms biophysics; Whole-Body Irradiation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-11-3828

Angiotensin 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.