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

Angiotensin II (Ang-II) exerts inflammatory activity and is involved in different cardiovascular disorders. This study has evaluated the involvement of tumor necrosis factor alpha (TNF␣) in the leukocyte accumulation elicited by Ang-II. Ang-II (1 nM intraperitoneally in rats) induced TNF␣ release at 1 hour followed by neutrophil and mononuclear cell recruitment. The administration of an antirat TNF␣ antiserum had no effect on Ang-IIinduced neutrophil accumulation but in- IntroductionAtherosclerosis is the major cause of myocardial infarction, stroke, and peripheral vascular disease, which accounts for nearly half of all mortality in developed countries. 1 Adhesive interactions between leukocytes and arterial endothelium precede leukocyte infiltration to the subendothelial space in pathological events such as atherosclerosis. 1,2 The migration of leukocytes from the blood to sites of extravascular injury is mediated through a sequential cascade of leukocyte-endothelial cell adhesive interactions that involve an array of cell adhesion molecules (CAMs) present on leukocytes and endothelial cells. 3 Interestingly, whereas leukocyteendothelial cell interactions in postcapillary venules are induced by a wide range of stimuli, leukocyte interactions with the arterial endothelium are only induced by certain risk factors for atherosclerosis such as cytokines like interleukin-1␤ (IL-1␤) or tumor necrosis factor alpha (TNF␣), oxidized low density lipoproteins (LDL), cigarette smoke, or angiotensin-II (Ang-II). [4][5][6][7][8] Activation of the renin-angiotensin system has been demonstrated in myocardial ischemia, acute myocardial infarction, coronary occlusion, and reperfusion models as well as in chronic left ventricular dysfunction after myocardial infarction. [9][10][11] Ang-II, the main effector peptide of the renin-angiotensin system, is implicated in atherogenesis beyond its hemodynamic effects. 12 We demonstrated that 4 hours of exposure to Ang-II in vivo caused arteriolar leukocyte adhesion in the rat mesenteric microcirculation through interaction with its AT 1 receptor subtype, 8 and this effect was not observed under acute (1-hour) stimulation with this peptide hormone. 13 Furthermore, mononuclear cells were found to be the primary cells attached to the arteriolar endothelium whereas the leukocytes interacting with the venular endothelium at the same time were predominantly neutrophils. Despite these findings, the same CAMs were expressed in both the arteriolar and venular endothelia in response to 8 suggesting that other mechanisms were responsible for the differential cellular distribution within the microcirculation.Therefore, this differential effect displayed by Ang-II may be due to different activation mechanisms. Thus, in postcapillary venules, the early response of neutrophil accumulation is primarily mediated by the direct effect of Ang-II on endothelial cells via the expression of P selectin and the rapid release of CXC chemokines. 13,14 In arterioles, leukocyte adhesion probably requires the addition...

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 mol/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. (Arterioscler Thromb Vasc Biol.