CXCR2 blockade impairs angiotensin II-induced CC chemokine synthesis and mononuclear leukocyte infiltration.
OBJECTIVE
Angiotensin II (Ang-II) and mononuclear leukocytes are involved in atherosclerosis. This study reports the inhibition of Ang-II-induced mononuclear cell recruitment by CXCR2 antagonism and the mechanisms involved.


RESULTS
Ang-II (1 nmol/L, i.p. in rats) induced CXC and CC chemokines, followed by neutrophil and mononuclear cell recruitment. Administration of the CXCR2 antagonist, SB-517785-M, inhibited the infiltration of both neutrophils (98%) and mononuclear cells (60%). SB-517785-M had no effect on the increase in CXC chemokine levels but reduced MCP-1, RANTES, and MIP-1alpha release by 66%, 63%, and 80%, respectively. Intravital microscopy showed that pretreatment with SB-517785-M inhibited Ang-II-induced arteriolar mononuclear leukocyte adhesion. Stimulation of human umbilical arterial endothelial cells (HUAECs) or whole blood with 1 micromol/L Ang-II induced the synthesis of chemokines. Ang-II increased HUAEC CXCR2 expression, and its blockade caused a significant reduction of MCP-1, -3, and RANTES release, as well as mononuclear cell arrest. Ang-II-induced MIP-1alpha release from blood cells was also inhibited.


CONCLUSIONS
Mononuclear leukocyte recruitment induced by Ang-II is, surprisingly, largely mediated by the CXC chemokines which appear to induce the release of CC chemokines. Therefore, CXC chemokine receptor antagonists may help to prevent mononuclear cell infiltration and the progression of the atherogenic process.
Abu Nabah
Yafa Naim
YN
Departments of Pharmacology, Faculty of Medicine, University Clinic Hospital, University of Valencia, Spain.
Losada
Mercedes
M
Estellés
Rossana
R
Mateo
Teresa
T
Company
Chantal
C
Piqueras
Laura
L
Lopez-Gines
Concha
C
Sarau
Henry
H
Cortijo
Julio
J
Morcillo
Esteban J
EJ
Jose
Peter J
PJ
Sanz
Maria-Jesus
MJ
D000804:Angiotensin II / Q000187:drug effects / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D054410:Chemokine CCL7; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D019808:Losartan / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000502:physiology; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013152:Splanchnic Circulation / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; C515450:CCL7 protein, human; C491766:Ccl2 protein, rat; C515452:Ccl7 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D023063:Receptors, Interleukin-8B; D000804:Angiotensin II; D019808:Losartan