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Captopril Inhibits the Proliferation of Hematopoietic Stem and Progenitor Cells in Murine Long-Term Bone Marrow Cultures

^a School of Biology, Medical Science & Human Biology, University of St. Andrews, Scotland, UK;
^b Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France

Key Words. Captopril • LTBMC • Hematopoietic stem cells • AcSDKP • AcSDKP analog • ACE

Correspondence: Dr. Joanna Wdzieczak-Bakala, ICSN, CNRS, 91198 Gif-sur-Yvette, France.

	Abstract

Top Abstract Introduction Material and Methods Results Discussion References

 
Drugs used mainly for the treatment of hypertension, such as angiotensin I-converting enzyme (ACE) inhibitors, can cause pancytopenia. The underlying cause of this side effect remains unknown. In the present study, long-term bone marrow cultures (LTBMCs) were utilized to evaluate the role of captopril (D-3-mercapto-2-methylpropionyl-L-proline), one of the potent ACE inhibitors, in regulating hematopoietic stem/progenitor cell proliferation. Captopril (10^-6 M final concentration) was added to LTBMCs at the beginning of the culture period and at weekly intervals for six weeks. There was no toxicity to the bone marrow cells as measured by the unchanged cell number in the nonadherent layer during the whole culture period, and there was an increased cellularity of the adherent layer at the end of the six weeks of treatment. However, captopril decreased the proportion of granulocyte-macrophage colony-forming cells (GM-CFCs) in S phase at weeks 2 and 3 as well as that of high proliferative potential colony-forming cells (HPP-CFCs) at week 3 in the nonadherent layer. There was no change in the kinetics of the GM-CFCs and HPP-CFCs present in the adherent layer. These results suggest that captopril causes myelosuppression by inhibiting hematopoietic cell proliferation of progenitor and stem cells rather than depleting cells of the bone marrow microenvironment.

	Introduction

Top Abstract Introduction Material and Methods Results Discussion References

 
Captopril is one of the angiotensin I-converting enzyme inhibitors (ACEIs) known to cause granulocytopenia [1-3], aplastic anemia [4], and pancytopenia [5, 6]. A number of different mechanisms were shown to be involved in drug-induced anemia. Most drugs cause anemia by immune-mediated mechanisms [7] leading to the destruction of red blood cells (hemolytic anemia). However, captopril rarely causes this type of hematological complication. This suggests that this drug causes pancytopenia by other unknown mechanisms. The underlying cause of pancytopenia induced by this ACEI remains unresolved.

Long-term bone marrow culture (LTBMC) appears to embody many of the features of hematopoietic cell regulation in vivo and closely resembles the environment in hematopoietic tissues [8, 9]. In vitro studies have shown that the cells of the adherent layer, either spontaneously or after activation, produce a number of positive soluble factors capable of maintenance, survival, proliferation, differentiation, and extensive self-renewal of hematopoietic cells [10-12]. Some endogenous negative regulators, such as macrophage inflammatory protein-1 [13], transforming growth factor-ß [14], and the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) [15], are also involved in the regulation of proliferative activity of primitive hematopoietic cells in LTBMCs.

The fact that hematopoiesis can be maintained for several weeks makes the LTBMC an ideal model for investigating the effects of drugs on hematopoietic tissues in vitro. The purpose of this study was to investigate whether captopril, a potent inhibitor of ACE, exhibited toxic effects on cells present in the two layers in LTBMCs and to examine the eventual effect of this drug on the proliferation of primitive hematopoietic cells. Changes in cell number in the nonadherent layers were monitored following two, three, and five weeks of treatment with captopril and after six weeks of treatment in the adherent layers. The results reported here indicate the absence of toxicity and the ability of captopril to reversibly inhibit the proliferation of hematopoietic stem and progenitor cells. This could explain, at least in part, the hematological depression appearing during chronic administration of ACEI. The eventual role of AcSDKP, an inhibitor of stem cell proliferation and a physiological substrate of ACE, in the control of stem cell proliferation reported for captopril is discussed.

	Material and Methods

Top Abstract Introduction Material and Methods Results Discussion References

 
Mice
All experiments were carried out using 8- to 12-week-old F1 mice (CBA/H x C57BL/6) bred and reared at the University of St. Andrews, Scotland, UK. Animals were killed by cervical dislocation, and their femurs were dissected out. The femur cellularity was approximately 1.2 x 10⁷ nucleated cells.

Establishment of Long-Term Bone Marrow Cultures
Each femur was flushed with Fischer's medium (GIBCO BRL; Paisley, UK) supplemented with 20% horse serum ([HS], Globepharm; Esther, Surrey, UK), 50 international units (IU) benzyl penicillin, 50 µg/ml streptomycin, 2 mM L-glutamine and 10^–6 M hydrocortisone (Sigma; Pool, Dorset, UK) (F20%HS PS/G Hydro) into a 25-cm² tissue culture flask (Nunc; Roskilde, Denmark). No attempt was made to make single-cell suspensions. Saline (Antigen Pharmaceuticals; Roscrea, Ireland) or captopril (10^–6 M final concentration) (Sigma), was added to the flasks containing 1.2 x 10⁶ nucleated cells/ml at the beginning of culture. Flasks were gassed with air/5% CO₂ before incubation at 33°C. Total media change (10 ml), addition of fresh captopril, and gassing was performed once a week. Cells from six flasks treated with saline or captopril were pooled for further analysis. Experimental analysis was performed with cells of the nonadherent layer collected at the end of weeks 2, 3, and 5. Adherent layer cells were removed using a cell scraper (Greiner, Frickenhausen, UK) at the end of week 6. Adherent cells were pooled in 10 ml of medium per flask for analysis.

Granulocyte-Macrophage Colony-Forming Cell (GM-CFC) Assay
Cells (5 x 10⁴ cells/ml) were suspended in Dulbecco's medium (GIBCO BRL) supplemented with 20% HS, 50 IU benzyl penicillin, 50 µg/ml streptomycin, and 2 mM L-glutamine (D20%HS PS/G) with 0.3% melted agar (Bacto Agar, Difco Labs; Detroit, MI). One ml of cell suspension was plated in each non-tissue culture grade 30-mm Petri dish (Sterilin; Stone, UK) in the presence of 40 U/ml, murine recombinant GM-CSF (Immunex; WA). Petri dishes were incubated in a fully humidified air/10% CO₂ incubator at 37°C for seven days. At the end of the incubation period, colonies of more than 50 cells were counted using a dark field microscope. The proportion of GM-CFC in S phase was determined by incubating cells with cytosine arabinoside (Ara-C) (25 µg/ml) (Sigma) for 1 h prior to plating.

High Proliferative Potential Colony-Forming Cell (HPP-CFC) Assay
The HPP-CFC assay was performed as previously described [16]. Briefly, cells were grown over a feeder made up of 0.5% melted agar (Bacto Agar, Difco Labs) in D20%HS PS/G supplemented with WEHI-3B- and L929-conditioned media used as a crude source of interleukin 3 and macrophage-colony stimulating factor. A cellular layer was made up of 5 x 10⁴ nucleated cells/ml in D20%HS PS/G with 0.3% melted agar. Cultures were incubated in a fully humidified air/10% CO₂ incubator at 37°C. On day 13, the vital stain 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride (BDH Chemicals Ltd.; Poole, UK) was added, and colonies (>2 mm) were counted on day 14. The proportion of HPP-CFC in S phase was determined by incubating cells with Ara-C (25 µg/ml) for 1 h prior to plating.

Statistical Analysis
Four independent studies were performed for each group of experiments. Cells from six pooled flasks were counted and analyzed for the proportion of GM-CFCs and HPP-CFCs in S phase. Hematopoietic cells from flasks were routinely plated in eight Petri dishes for GM-CFC and four Petri dishes for HPP-CFC. Therefore, colonies in 64 Petri dishes for GM-CFC S-phase assay and colonies in 32 Petri dishes for HPP-CFC S-phase assay at each week were counted. The statistical significance of the results was determined by the unpaired Students' t-test. A p-value of 0.05 or less was considered significant.

	Results

Top Abstract Introduction Material and Methods Results Discussion References

 
Effect of Captopril on the Number of Cells Present in Nonadherent and Adherent Layers of LTBMCs
The number of nucleated cells in LTMBC nonadherent layers was determined at the end of weeks 2, 3, and 5 of culture. As shown in Figure 1A, there was no difference in cell counts between saline- and captopril-treated cultures examined at weeks 2, 3, and 5. However, a statistically significant increase in cellularity of the adherent layer was observed in LTBMCs after six weeks of treatment with captopril. As shown in Figure 1B, the number of cells per flask in the adherent layers of the saline- and captopril-treated cultures was respectively (23.8 ± 2.7) x 10⁶ and (33 ± 2.1) x 10⁶ (p < 0.05).

View larger version (24K): [in this window] [in a new window]   Figure 1. Effect of captopril on the number of cells present in (A) the nonadherent and (B) the adherent layers of LTBMCs. Results represent the mean ± SE of four independent experiments. There was a significant difference between the cellularity of the adherent layer in the saline- and captopril-treated groups on week 6 (*p < 0.05).

View larger version (25K): [in this window] [in a new window]   Figure 2. The effect of captopril on the proportion of GM-CFCs in S phase present in (A) the nonadherent layer and (B) the adherent layer of LTBMCs. Results represent the mean ± SE of four independent experiments. There was a significant difference in the proportion of GM-CFC in S phase in the nonadherent layer on weeks 2 and 3 of the captopril-treated group (*p < 0.05).

Effect of Captopril on the Proliferation of HPP-CFCs Present in Nonadherent and Adherent Layers of LTBMCs
Treatment of LTBMCs with captopril for two weeks induced no significant change in the percentage of HPP-CFCs in S phase present in the nonadherent layer, as shown in Figure 3A. The proportion of HPP-CFCs in S phase was 40.8 ± 11% and 24.1 ± 9.5%, respectively, in the saline- and captopril-treated cultures. However, after three weeks of treatment with captopril, a significant inhibition of HPP-CFC proliferation from 24.1 ± 3.4% in the control cultures to only 6.6 ± 3.8% in the captopril-treated cultures (p < 0.05) was noted. At week 5, the proportion of HPP-CFCs in S phase in the control (47 ± 9.8%) and in the captopril-treated cultures (25.2 ± 10%) was not significantly different.

View larger version (23K): [in this window] [in a new window]   Figure 3. The effect of captopril on the proportion of HPP-CFCs in S phase present in (A) the nonadherent and (B) adherent layer of LTBMCs. Results represent the mean ± SE of four independent experiments. There was a significant difference in the proportion of HPP-CFCs in S phase in the nonadherent layer on week 3 of the captopril-treated group (*p < 0.05).

	Discussion

Top Abstract Introduction Material and Methods Results Discussion References

 
Hematological depression associated with the administration of ACEIs, although rare, is an important side effect of these drugs. The adverse effects of ACEI therapy are resolved rapidly after the drug is withdrawn. Therefore, the careful hematological surveillance of patients treated with ACEIs was suggested. In order to determine the mechanism of hematological toxicity induced by these drugs, we have evaluated the effects of captopril, one of the specific inhibitors of ACE, on hematopoiesis in LTBMCs. However, the standard method of feeding LTBMCs with half media change [8] was replaced by feeding with total media change. This procedure was carried out to ensure that a known concentration of captopril was available to cells at the beginning of each week of culture. In vitro hematopoiesis did not seem to be modified under these experimental conditions. Captopril was used at 10^–6 M, as this concentration was shown to inhibit HPP-CFC-1 proliferation in preliminary studies.

The results reported here show that captopril did not reduce the nucleated cell number in the adherent as well as in nonadherent cell layers. However, it inhibited the proliferation of the nonadherent GM-CFCs and HPP-CFCs while it had no effect on the proliferative state of these cells present in the adherent layer of LTMBCs.

Captopril has been previously shown to decrease transforming growth factor-ß (TGF-ß) receptor type I and II expression [17]. Thus, TGF-ß produced in LTBMC in the presence of captopril may be ineffective in regulating hemopoiesis. Captopril is also a potent free radical scavenger [18], and the suppressive effect of this drug on granulopoiesis has been attributed to its antioxidative characteristics [19]. Among the potential routes by which captopril could affect primitive hematopoietic cell proliferation, the control of AcSDKP level by this drug cannot be ignored.

The tetrapeptide AcSDKP belongs to a family of negative regulators of hematopoiesis [20]. It inhibits in vivo and in vitro the entry into S phase of human and murine stem cells and committed progenitors [20-22]. AcSDKP has recently been shown to be a physiological substrate of the N-terminal active site of ACE [23-25]. Thus, the presence of this tetrapeptide both in vitro and in vivo is largely preserved in the presence of ACEI [25-27]. Taking into consideration a steady-state production of AcSDKP in LTBMCs [28, 29] and the fact that ACE is produced by macrophages [30] which form a part of the adherent layer of LTBMCs [8], it is highly probable that captopril indirectly controls the proliferation of HPP-CFC and GM-CFC via the upregulation of the endogenous AcSDKP level. In fact, the inhibition of the proliferation of hematopoietic stem cells and committed progenitors in LTBMCs treated with AcSDKP is well documented [31-33]. It has to be stressed that the observed absence of the inhibitory effect of captopril on the cells present in the adherent layer of LTBMCs is in total agreement with the data reported by Jackson et al. [33], who showed that AcSDKP prevented selectively the entry into S phase of HPP-CFCs present only in the nonadherent layer. Moreover, it has been reported previously that the concentration of AcSDKP is critical in obtaining a biological effect [21, 22], and particularly it has been shown that, in LTBMCs, an optimal concentration of AcSDKP is required to obtain the inhibition of HPP-CFC proliferation [33]. This may be the reason for the varying effects of captopril on HPP-CFC proliferation in LTBMCs throughout the treatment period. In fact, it cannot be excluded that the lack of inhibitory effect of captopril on HPP-CFC proliferation observed at weeks 2 and 5 is tightly linked with the number of macrophages purported to be the cell population secreting AcSDKP in LTBMC [29]. Since captopril efficiently blocks the catalytic activity of ACE present in culture medium with 20% HS and thus prevents the degradation of locally produced AcSDKP, no effect of this drug on the proliferative state of HPP-CFCs at week 2 of LTBMC could be due to the insufficient concentration of endogenous AcSDKP secreted by the low number of macrophages. However at week 5, when the increased number of macrophages is supposed to produce a higher concentration of AcSDKP, captopril had no inhibitory effect on HPP-CFC proliferation. Therefore, it is probable that only at week 3, when the optimal concentration of AcSDKP in LTBMC is available, that captopril can prevent HPP-CFC proliferation. The same explanation can be proposed for the description of the varying effect of captopril on GM-CFC proliferation. The results we have obtained with a biologically active analog of AcSDKP, the pseudopeptide AcSDKP resistant to the proteolysis by ACE and thus stable in biological fluids [34], also support the hypothesis of the role of AcSDKP as a mediator of captopril antiproliferative activity. In fact, it has been demonstrated that AcSDKP tested at the concentration 10^–9 M, the dose defined previously as optimal for obtaining the inhibitory activity [35], was able to prevent the proliferation of HPP-CFC during the whole period studied from week 2 and to week 5 (data not shown).

In any case, the fact that the effect of captopril on HPP-CFC proliferation exhibited the same trend as the one observed with AcSDKP [31-33] strengthens the hypothesis of indirect control of hematopoietic cell proliferation by captopril. Thus, ACEI preventing the hydrolysis of endogenous AcSDKP in LTBMCs could maintain or upregulate the level of this tetrapeptide, which then exerts its antiproliferative effect. The close correlation between the enhanced plasma AcSDKP levels and the inhibition of HPP-CFC proliferation reported for irradiated mice given one dose of lisinopril, an alternative ACEI, is in agreement with such a hypothesis [36].

In conclusion, we have shown that the hematological depression induced in vivo by captopril, one of the specific inhibitors of ACE, could be due, at least in part, to inhibition of the proliferation of hematopoietic stem/progenitor cells by this drug. The reported antiproliferative effect of captopril also suggests its therapeutic application in vitro as an adjuvant to purging methods to prevent short-term myelotoxicity. To further assess the biological potential of captopril and to precisely define its mode of action, in vivo studies with this drug will be undertaken.

	Acknowledgments

 
We thank Katharina Broetz for her help in the typing of the manuscript, Dr. C. Peddie for critical review of the manuscript, and Ms. J. Melville for her technical support. We are grateful to the World Health Organization and CNRS/Royal Society for their financial support.

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