title: Myelopoiesis modulation by ACE hyperfunction in kinin B(1) receptor knockout mice: relationship with AcSDKP levels.
abstract: Angiotensin I-converting enzyme (ACE), a common element of renin-angiotensin system (RAS) and kallikrein-kinin system (KKS), is involved in myelopoiesis modulation, mainly by cleaving the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). Based on this finding and in our results showing B1 and B2 kinin receptors expression in murine bone marrow (BM) cells, we evaluated the ACE influence on myelopoiesis of kinin B1 receptor knockout mice (B1KO) using long-term bone marrow cultures (LTBMCs). Captopril and AcSDKP were used as controls. Enhanced ACE activity, expressed by non-hematopoietic cells (Ter-199(-) and CD45(-)), was observed in B1KO LTBMCs when compared to wild-type (WT) cells. ACE hyperfunction in B1KO cells was maintained when LTBMCs from B1KO mice were treated with captopril (1.0microM) or AcSDKP (1.0nM). Although no alterations were observed in ACE mRNA and protein levels under these culture conditions, 3.0nM of AcSDKP increased ACE mRNA levels in WT LTBMCs. No alteration in the number of GM-CFC was seen in B1KO mice compared to WT animals, even when the former were treated with AcSDKP (10microg/kg) or captopril (100mg/kg) for 4 consecutive days. Hematological data also revealed no differences between WT and B1KO mice under basal conditions. When the animals received 4 doses of lipopolysaccharide (LPS), a decreased number of blood cells was detected in B1KO mice in relation to WT. We also found a decreased percentage of Gr1(+)/Mac-1(+), Ter119(+), B220(+), CD3(+), and Lin(-)Sca1(+)c-Kit(+) (LSK) cells in the BM of B1KO mice compared to WT animals. Low AcSDKP levels were observed in BM cultures from B1KO in comparison to WT cultures. We conclude that ACE hyperfunction in B1KO mice resulted in faster hydrolysis of AcSDKP peptide, which in turn decreased in BM tissues allowing HSC to enter the S stage of the cell cycle.
authors.affiliation: Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua 3 de maio, 100, 04040-020 São Paulo, SP, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Edgar J
authors.initials: EJ
authors.lastname: Paredes-Gamero
authors.forename: Christiano M V
authors.initials: CM
authors.lastname: Barbosa
authors.forename: Fábio D
authors.initials: FD
authors.lastname: Nascimento
authors.forename: Elice C
authors.initials: EC
authors.lastname: Batista
authors.forename: Felipe C G
authors.initials: FC
authors.lastname: Reis
authors.forename: Antonio H B
authors.initials: AH
authors.lastname: Martins
authors.forename: Alice T
authors.initials: AT
authors.lastname: Ferreira
authors.forename: Adriana K
authors.initials: AK
authors.lastname: Carmona
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Ivarne L S
authors.initials: IL
authors.lastname: Tersariol
authors.forename: Ronaldo C
authors.initials: RC
authors.lastname: Araújo
authors.forename: Claudia
authors.initials: C
authors.lastname: Bincoletto
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D016234:Kallikrein-Kinin System; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System
chemical_list: D008070:Lipopolysaccharides; D009842:Oligopeptides; D043783:Receptor, Bradykinin B1; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; C058504:goralatide