Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors

Blockade of the renin-angiotensin system (RAS) is well recognized as an essential therapy in hypertensive, heart, and kidney diseases. There are several classes of drugs that block the RAS; these drugs are known to exhibit antifibrotic action. An analysis of the molecular mechanisms of action for these drugs can reveal potential differences in their antifibrotic roles. In this review, we discuss the antifibrotic action of RAS blockade with an emphasis on the potential importance of angiotensin I-converting enzyme (ACE) inhibition associated with the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP)

Optimization of cell culture conditions for the evaluation of the biological activities of the tetrapeptide N-Acetyl-Ser-Asp-Lys-Pro, a natural hemoregulatory factor.

International audienceThe present study attempts to define the difficulties in evaluating the properties of the hemoregulatory peptide AcSDKP using in vitro assays. In fact, in the presence of sera, which are generally added to basic culture media, AcSDKP is catabolized by proteases present in the serum. The kinetics of AcSDKP degradation depends on the nature and on the concentration of the added serum. In in vitro conditions, the half life of this peptide can be increased by the addition of 1 microM captopril, a metalloprotease inhibitor. Thus, these points need to be considered in designing experiments to study the effects of AcSDKP

Inhibitory action of the peptide AcSDKP on the proliferative state of haematopoietic stem cells in the presence of captopril but not lisinopril

The effect of Angiotensin I-converting enzyme (ACE) inhibitors on their own and in combination with the peptide AcSDKP on the proliferation of hematopoietic stem cells has been investigated. Hematopoietic stem cells from murine bone marrow induced into cell cycle following exposure to 2 Gy gamma-irradiation were incubated in vitro for up to 24 h in the presence of medium, captopril/lisinopril, AcSDKP, and AcSDKP with either ACE inhibitor, Hematopoietic stem cells were monitored using the high proliferative potential-colony forming cell-1 (HPP-CFC-1) population cloned in the presence of human IL-I beta, murine IL-3, and murine M-CSF. No significant inhibitory effect was observed in the presence of AcSDKP on its own and AcSDKP in combination with lisinopril, However, there was a significant inhibition of stem cell cycling when AcSDKP and captopril were combined, This suggests that captopril inhibits AcSDKP breakdown better than lisinopril, The combination of AcSDKP and captopril also had an inhibitory effect on cell recruitment into S phase, The fact that a combination of AcSDKP and captopril snitches cycling hematopoietic stem cells out of cycle indicates the importance of the N-active catalytic site of ACE in AcSDKP hydrolysis in vitro, Thus, AcSDKP in combination with appropriate ACE inhibitors may be of use in regulating the proliferation of hematopoietic stern cells in vitro.</p

Inhibitory action of the peptide AcSDKP on the proliferative state of haematopoietic stem cells in the presence of captopril but not lisinopril

The effect of Angiotensin I-converting enzyme (ACE) inhibitors on their own and in combination with the peptide AcSDKP on the proliferation of hematopoietic stem cells has been investigated. Hematopoietic stem cells from murine bone marrow induced into cell cycle following exposure to 2 Gy gamma-irradiation were incubated in vitro for up to 24 h in the presence of medium, captopril/lisinopril, AcSDKP, and AcSDKP with either ACE inhibitor, Hematopoietic stem cells were monitored using the high proliferative potential-colony forming cell-1 (HPP-CFC-1) population cloned in the presence of human IL-I beta, murine IL-3, and murine M-CSF. No significant inhibitory effect was observed in the presence of AcSDKP on its own and AcSDKP in combination with lisinopril, However, there was a significant inhibition of stem cell cycling when AcSDKP and captopril were combined, This suggests that captopril inhibits AcSDKP breakdown better than lisinopril, The combination of AcSDKP and captopril also had an inhibitory effect on cell recruitment into S phase, The fact that a combination of AcSDKP and captopril snitches cycling hematopoietic stem cells out of cycle indicates the importance of the N-active catalytic site of ACE in AcSDKP hydrolysis in vitro, Thus, AcSDKP in combination with appropriate ACE inhibitors may be of use in regulating the proliferation of hematopoietic stern cells in vitro.</p

The antiproliferative activity of the tetrapeptide Acetyl-N-SerAspLysPro, an inhibitor of haematopoietic stem cell proliferation, is not mediated by a thymosin beta 4-like effect on actin assembly.

International audienceAcetyl-N-SerAspLysPro (AcSDKP), known as a negative regulator of haematopoiesis, has been principally reported as an inhibitor of haematopoietic pluripotent stem cell proliferation. The tetrapeptide sequence is identical to the N-terminus of thymosin beta 4 (T beta 4), from which it has been suggested that it may be derived. Recently, evidence was shown that T beta 4 plays a role as a negative regulator of actin polymerization leading to the sequestration of its monomeric form. The structural similarity between the N-terminus of T beta 4 and AcSDKP has raised the possibility that AcSDKP may also participate in intracellular events leading to actin sequestration. The effect of T beta 4 on the proliferation of haematopoietic cells was compared to that of AcSDKP. The results revealed that T beta 4, like AcSDKP, exerts an inhibitory effect on the entry of murine primitive bone marrow cells into cell cycle in vitro. Qualitative electrophoretic analysis and quantitative polymerization assays were used to investigate the role of AcSDKP in actin polymerization. AcSDKP does not affect actin assembly at concentrations up to 50 microM, and does not compete with T beta 4 for binding to G-actin. These results suggest that AcSDKP is not involved in cell cycle regulation via an effect on the process of actin polymerization