on August 23, 2007
Published online before print August 23, 2007, doi: 10.1161/ATVBAHA.107.147009
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Submitted on April 25, 2007
Accepted on July 25, 2007
CXCR2 Blockade Impairs Angiotensin II–Induced CC Chemokine Synthesis and Mononuclear Leukocyte Infiltration
Yafa Naim Abu Nabah ;
From the Departments of Pharmacology (Y.N.A.N., M.L., R.E., T.M., C.C., J.C., E.J.M., P.J.J., M.-J.S.) and Pathology (C.L.-G.), Faculty of Medicine, and the Research Foundation (L.P., E.J.M.), University Clinic Hospital, University of Valencia, Spain; Glaxo Smith Kline (H.S.), Pa; the Research Foundation (J.C.), University General Hospital Consortium, Valencia, Spain; and Ciber CB06/06/0027 "Respiratory Diseases" Carlos III Health Institute (J.C., E.J.M., M.-J.S.), Spanish Ministry of Health, Spain.
* To whom correspondence should be addressed. E-mail: maria.j.sanz{at}uv.es.
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.
Methods and 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-1
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 µmol/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-1 release from blood cells was also inhibited.
Conclusion—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.
Key words: angiotensin-II • chemokines • leukocytes • microcirculation • inflammation
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