Captopril inhibitsin vitroandin vivothe proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation

Abstract

Angiotensin I‐converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl‐Ser–Asp–Lys–Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10−6 m captopril. Captopril significantly reduced the proportion of high proliferative potential colony‐forming cells (HPP‐CFC‐1) in S‐phase, whereas it had no effect on the proportion of SA2 leukaemic colony‐forming cells in S‐phase. When given in vivo to mice 1 h after 2 Gy γ‐irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP‐CFC‐1 entry into S‐phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril‐treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.

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

“…For example, ACE inhibition reduced the ability of embryoid bodies to generate hematopoietic colony-forming cells by blocking hemangioblast expansion and differentiation toward either the endothelium or multipotent hematopoietic progenitors (Zambidis et al, 2008). Acute ACE inhibitor administration in mice prevented potential colony-forming cells from entering the cell cycle, and thus protected these cells from the lethal effects of chemotherapy or irradiation (Chisi et al, 2000). Further in vivo analysis of an irradiation model showed that ACE inhibitors preserved stem cells and bone marrow multilineage hematopoietic progenitors, including colony-forming unit (CFU) granulocyte/ macrophage, burst-forming unit erythroid, and CFU megakaryocyte (Charrier et al, 2004).…”

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

“…23 When BM from the mice treated with irradiation or chemotherapy were examined, ACE inhibition prevented HPP-CFC from entering cell cycle in an ex vivo culture. 75 In a sublethal irradiation model, short-term peri-radiation treatment with ACE inhibitor perindopril increased BM multi-lineage hematopoietic progenitors (CFU-GM, BFU-E and CFU-MK) and helped preserving shortterm reconstituting cells. 76 These data are reminiscent of the actions attributed to Ac-SDKP.…”

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

“…Angiotensin II may directly act on the stem cell compartment by promoting entry into the cell-cycle entry. [24][25][26] Alternatively, angiotensin II may indirectly regulate the stem cell compartment by acting on the hematopoietic niche. For example, inhibition of the angiotensin II signaling pathway reduces the production of several cytokines such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor ␤1 (TGF␤1).…”

“…22,23 ACE inhibitors prevent the entry of murine hematopoietic stem cells into the cell cycle after irradiation 24 and inhibit the proliferation of hematopoietic stem and progenitor cells in long-term bone marrow culture. 25,26 Thus, pharmacologic inhibition of ACE may interfere with hematopoiesis.…”