<i>In vivo</i> haemoprotective activity of tetrapeptide AcSDKP combined with granulocyte‐colony stimulating factor following sublethal irradiation

Watanabe, Tsutomu; Kelsey, Linda; Yan, Yun; Brown, Geoffrey; Jackson, John D.; Ewel, Cynthia; Talmadge, James E.

doi:10.1046/j.1365-2141.1996.d01-1853.x

Cited by 24 publications

(28 citation statements)

References 28 publications

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“…Thus, one can envisage controlling plasma AcSDKP levels without interfering with blood pressure control. Taking into consideration the important role of AcSDKP in the control of the hematopoietic cycle (11), inhibition of the N-terminal ACE active site may have important clinical applications in facilitating hematopoietic recovery after aggressive cancer chemotherapy (32)(33)(34)(35). The in vivo stability of RXP 407, as well as its pharmacokinetic properties, should allow us to address this issue in the near future.…”

Section: Discussionmentioning

confidence: 99%

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Dive

Cotton²,

Yiotakis³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

171

186

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The human somatic angiotensin converting enzyme (ACE) contains two homologous domains, each bearing a zinc-dependent active site. All of the synthetic inhibitors of this enzyme used in clinical applications interact with these two active sites to a similar extent. Recently, several lines of evidence have suggested that the N-terminal active site of ACE might be involved in specific hydrolysis of some important physiological substrates, like Acetyl-Seryl-Aspartyl-LysylProline, a negative regulator of hematopoietic stem cell differentiation and proliferation. These findings have stimulated studies aimed at identifying new ACE inhibitors able to block only one of the two active sites of this enzyme. By screening phosphinic peptide libraries, we discovered a phosphinic peptide Ac-Asp-(L) Phe(PO 2 -CH 2 ) (L) Ala-Ala-NH 2 , called RXP 407, which is able to differentiate the two ACE active sites, with a dissociation constant three orders of magnitude lower for the N-domain of the enzyme. The usefulness of a combinatorial chemistry approach to develop new lead structures is underscored by the unusual chemical structure of RXP 407, as compared with classical ACE inhibitors. As a highly potent and selective inhibitor of the N-terminal active site of wild ACE (K i ‫؍‬ 12 nM), RXP 407, which is metabolically stable in vivo, may lead to a new generation of ACE inhibitors able to block in vivo only a subset of the different functions regulated by ACE.

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Section: Discussionmentioning

confidence: 99%

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Dive

Cotton²,

Yiotakis³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

171

186

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“…After surgery, an osmotic minipump (Alzet 2 ML4, Alza Corp) was implanted subcutaneously in the neck to deliver either Ac-SDKP (Bachem) or saline plus 0.01N acetic acid, 20 basing the route of administration and dosage on previous studies. 21,22 Rats were subdivided into 4 groups: (1) …”

Section: K-1c Hypertensionmentioning

confidence: 99%

Long-Term Effect of N -Acetyl-Seryl-Aspartyl-Lysyl-Proline on Left Ventricular Collagen Deposition in Rats With 2-Kidney, 1-Clip Hypertension

et al. 2001

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Background-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation. Ac-SDKP plasma concentration is increased 5-fold after angiotensin-converting enzyme inhibition. Here we studied the effect of Ac-SDKP on monocyte/macrophage infiltration, fibroblast proliferation, and collagen deposition in the rat heart in renovascular hypertension. Methods and Results-We investigated whether long-term Ac-SDKP administration would prevent left ventricular (LV) hypertrophy and interstitial collagen deposition in rats with 2-kidney, 1-clip (2K-1C) hypertension. Ac-SDKP (400 g · kg Ϫ1 · d Ϫ1 ) did not affect development of hypertension. Mean blood pressure was similar in rats with 2K-1C hypertension whether they were given vehicle or Ac-SDKP and was higher than in controls. Both LV weight and cardiomyocyte size were significantly increased in rats with 2K-1C hypertension compared with controls and were unaffected by Ac-SDKP. Proliferating cell nuclear antigen-and monocyte/macrophage-positive cells were increased in the LV of 2K-1C hypertensive rats; this increase was significantly blunted by Ac-SDKP (PϽ0.001). LV interstitial collagen fraction was also increased in 2K-1C hypertensive rats given vehicle (10.1Ϯ0.8%) compared with sham (5.3Ϯ0.1%, PϽ0.0001), and this increase was prevented by Ac-SDKP (5.4Ϯ0.4%, PϽ0.001). Conclusions-Ac-SDKP inhibited monocyte/macrophage infiltration, cell proliferation, and collagen deposition in the LV of hypertensive rats without affecting blood pressure or cardiac hypertrophy, suggesting that it may be partly responsible for the cardioprotective effect of angiotensin-converting enzyme inhibitors.

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“…Specifically, Ac-SDKP treatment increased animal survival rate, BM hematopoietic progenitor number and peripheral cell counts in animals treated with cytotoxic agents or ionizing radiation. [56][57][58][59] That this protection is due to the reversible blockage of cell cycle comes from the observations that maximum protective effects were achieved when Ac-SDKP was administered at least 24 hours before, but not after, the start of irradiation or ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

mentioning

confidence: 99%

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

Shen

Bernstein

2011

Cell Cycle

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T he concept of a local bone marrow renin-angiotensin system (RAS) has been introduced and accumulating evidence suggests that the local RAS is actively involved in hematopoiesis. Angiotensin converting enzyme (ACE) is a key player in the RAS and makes the final effector angiotensin II. Besides angiotensin II, ACE also regulates a panel of bioactive peptides, such as substance P, Ac-SDKP and angiotensin 1-7. These peptides have also been individually reported in the regulation of pathways of hematopoiesis. In this setting, an ACE-regulated peptide network orchestrating hematopoiesis has emerged. Here, we focus on this peptide network and discuss the roles of ACE and its peptides in aspects of hematopoiesis. Special attention is given to the recent revelation that ACE is a bona fide marker of hematopoietic stem cells.

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In vivo haemoprotective activity of tetrapeptide AcSDKP combined with granulocyte‐colony stimulating factor following sublethal irradiation

Cited by 24 publications

References 28 publications

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Long-Term Effect of N -Acetyl-Seryl-Aspartyl-Lysyl-Proline on Left Ventricular Collagen Deposition in Rats With 2-Kidney, 1-Clip Hypertension

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

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