ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-Salt rats

被引:47
作者
Callera, GE
Montezano, AC
Touyz, RM
Zorn, TMT
Carvalho, MHC
Fortes, ZB
Nigro, D
Schiffrin, EL
Tostes, RC
机构
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo, Brazil
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Histol & Embryol, BR-05508900 Sao Paulo, Brazil
[3] Univ Montreal, Clin Res Inst Montreal, Montreal, PQ, Canada
关键词
endothelin; deoxycorticosterone; arterial; hypertension; leukocytes; cell adhesion molecules;
D O I
10.1161/01.HYP.0000117296.30296.14
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ETA receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ETA antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ETA antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ETA receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.
引用
收藏
页码:872 / 879
页数:8
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