Negative regulator of pluripotent hematopoietic stem cell proliferation in human white blood cells and plasma as analysed by enzyme immunoassay

Pradelles, Philippe; Frobert, Yveline; Créminon, Christophe; Liozon, É.; Massé, Aline; Frindel, E

doi:10.1016/0006-291x(90)90489-a

Cited by 78 publications

(58 citation statements)

References 11 publications

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“…Urine AcSDKP concentration was determined by a competitive enzyme immunoassay (15) and was used as a marker of in vivo tubular ACE inhibition (16).…”

Section: Laboratory Methodsmentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

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“…Urine AcSDKP concentration was determined by a competitive enzyme immunoassay (15) and was used as a marker of in vivo tubular ACE inhibition (16).…”

Section: Laboratory Methodsmentioning

confidence: 99%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Recovered plasma was stored at Ϫ70°C until the Ac-SDKP assay was performed. Plasma Ac-SDKP was quantified with a competitive enzyme immunoassay 5 and expressed as nanomoles per liter.…”

Section: Ac-sdkp Plasma Levelsmentioning

confidence: 99%

“…1,2 Ac-SDKP naturally inhibits entry of pluripotent hematopoietic stem cells into the S phase, instead maintaining them in the G 0 /G 1 phase and thus blocking DNA synthesis. 3,4 This tetrapeptide is normally present in human plasma and circulating mononuclear cells 5 and is widely distributed in vivo. 6 Angiotensin-converting enzyme (ACE) has 2 homologous NH 2 -and COO-terminal catalytic domains.…”

mentioning

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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“…[1][2][3] It was originally described as a natural inhibitor of pluripotent hematopoietic stem cells, preventing entry into the S phase. 4 Recently, Ac-SDKP was found to be hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE).…”

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confidence: 99%

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

et al. 2004

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Abstract-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-␤ 4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-␤ 4 : prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-␤ 4 , and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76Ϯ0.2 to 1.01Ϯ0.1 nM), heart (from 2.31Ϯ0.21 to 0.83Ϯ0.09 pmol/mg protein), and kidneys (from 5.62Ϯ0.34 to 2.86Ϯ0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide

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Negative regulator of pluripotent hematopoietic stem cell proliferation in human white blood cells and plasma as analysed by enzyme immunoassay

Cited by 78 publications

References 11 publications

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Physiologic Consequences of Vasopeptidase Inhibition in Humans

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

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

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