Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline.
Angiotensin I-converting enzyme (ACE) has two homologous active NH2- and COOH-terminal domains and displays activity toward a broad range of substrates. The tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has been shown to be hydrolyzed in vitro by ACE and to be a preferential substrate for its NH2-terminal active site. This peptide is a regulatory factor of hematopoiesis which reversibly stem cells and normal early progenitors into S-phase. We found that a single oral dose of 50 mg of the ACE inhibitor, captopril, when administered to eight healthy subjects in a double-blind, crossover, placebo-controlled study, massively increased the plasma level of Ac-SDKP. ACE inhibition by captopril induced a 90-99% inhibition of in vitro [3H]Ac-SDKP hydrolysis and a long-lasting 5.5-fold (range: 4-8.5-fold) increase in the plasma levels of Ac-SDKP. These results demonstrate that Ac-SDKP is the first natural peptide hydrolyzed by the NH2-terminal domain of ACE not only in vitro but also in vivo, confirming that both catalytic sites of ACE are physiologically active. Our data suggest that ACE may also be implicated in the process of hematopoietic stem cell regulation, by permanently degrading this natural circulating inhibitor of cell entry into S-phase.
Azizi
M
M
Centre d'Investigations Cliniques, Hôpital Broussais, Paris, France.
Rousseau
A
A
Ezan
E
E
Guyene
T T
TT
Michelet
S
S
Grognet
J M
JM
Lenfant
M
M
Corvol
P
P
Ménard
J
J
D000284:Administration, Oral; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006131:Growth Inhibitors / Q000097:blood*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D006801:Humans; D006868:Hydrolysis; D008297:Male; D009842:Oligopeptides / Q000097:blood*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010919:Placebos; D012084:Renin-Angiotensin System / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D006131:Growth Inhibitors; D009842:Oligopeptides; D010919:Placebos; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; C058504:goralatide