Published Online
on November 29, 2004

A more recent version of this article appeared on December 7, 2004

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Submitted on June 23, 2004
Revised on August 30, 2004
Accepted on September 9, 2004

Angiotensin II Induces Neutrophil Accumulation In Vivo Through Generation and Release of CXC Chemokines

Yafa Naim Abu Nabah BPharm, Teresa Mateo BPharm, Rossana Estellés BPharm, PhD, Manuel Mata BSc, PhD, John Zagorski BSc, PhD, Henry Sarau BSc, PhD, Julio Cortijo BPharm, PhD, Esteban J. Morcillo MD, PhD, Peter J. Jose BSc, PhD, and Maria-Jesus Sanz BPharm, PhD^*

From the Department of Pharmacology (Y.N.A.N., T.M., R.E., M.M., J.C., E.J.M., M.-J.S.), Faculty of Medicine, University of Valencia, Valencia, Spain; the Carolinas Medical Center (J.Z.), Charlotte, NC; GlaxoSmithKline (H.S.), King of Prussia, Pa; the Valencia General Hospital Foundation, General Hospital of Valencia (J.C.), Valencia, Spain; and the Department of Leukocyte Biology (P.J.J.), School of Biomedical Sciences, Imperial College, London, UK.

^* To whom correspondence should be addressed. E-mail: maria.j.sanz{at}uv.es.

Background--Angiotensin II (Ang II) is implicated in the development of cardiac ischemic disorders in which prominent neutrophil accumulation occurs. Ang II can be generated intravascularly by the renin-angiotensin system or extravascularly by mast cell chymase. In this study, we characterized the ability of Ang II to induce neutrophil accumulation.

Methods and Results--Intraperitoneal administration of Ang II (1 nmol/L) induced significant neutrophil recruitment within 4 hours (13.3±2.3x10⁶ neutrophils per rat versus 0.7±0.5x10⁶ in control animals), which disappeared by 24 hours. Maximal levels of CXC chemokines were detected 1 hour after Ang II injection (577±224 pmol/L cytokine-inducible neutrophil chemoattractant [CINC]/keratinocyte-derived chemokine [KC] versus 5±3, and 281±120 pmol/L macrophage inflammatory protein [MIP-2] versus 14±6). Intravital microscopy within the rat mesenteric microcirculation showed that the short-term (30 to 60 minutes) leukocyte-endothelial cell interactions induced by Ang II were attenuated by an anti-rat CINC/KC antibody and nearly abolished by the CXCR2 antagonist SB-517785-M. In human umbilical vein endothelial cells (HUVECs) or human pulmonary artery media in culture, Ang II induced interleukin (IL)-8 mRNA expression at 1, 4, and 24 hours and the release of IL-8 at 4 hours through interaction with Ang II type 1 receptors. When HUVECs were pretreated with IL-1 for 24 hours to promote IL-8 storage in Weibel-Palade bodies, the Ang II-induced IL-8 release was more rapid and of greater magnitude.

Conclusions--Ang II provokes rapid neutrophil recruitment, mediated through the release of CXC chemokines such as CINC/KC and MIP-2 in rats and IL-8 in humans, and may contribute to the infiltration of neutrophils observed in acute myocardial infarction.

Key words: angiotensin • interleukins • cells • endothelium • inflammation

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