CXCR2 Blockade Impairs Angiotensin II–Induced CC Chemokine Synthesis and Mononuclear Leukocyte Infiltration

Abstract

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.

Neutrophil-Derived Matrix Metalloproteinase 9 Triggers Acute Aortic Dissection

“…Indeed, recent studies indicate that AngII can induce neutrophil infiltration. 22,23 In addition, AngII is also able to activate neutrophils and stimulate the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent production of reactive oxygen metabolites, which may promote the oxidative autoactivation of pro-MMP9. 48,49 In the current study, we could show the gelatinolytic metalloproteinase activity and superoxide production in the neutrophil-infiltrated dissecting aortic tissue from the BAPN/AngII-treated mice.…”

“…21 In addition, AngII is known to promote neutrophil infiltration into vascular walls, 22,23 and to induce MMP9 expression in cell types such as vascular smooth muscle cells. 24 Thus, we also measured the AngII levels in serum samples of the control, nonruptured aneurysm, AMI, and AAD groups, and found that the circulating AngII level was significantly higher in the AAD and AMI groups relative to the other groups studied (Figure 1).…”

Regulation of Atherogenesis by Chemokines and Chemokine Receptors

“…SB-517785-M (Glaxo-Smith-Kline) is an antagonist that selectively inhibits CXCR2. This agent significantly reduced angiotensin II-induced infiltration of mononuclear cells and neutrophils into rat arterioles, suggesting that it may inhibit atherogenesis by controlling recruitment of neutrophils into the vessel wall (Nabah et al 2007; Drechsler et al 2011). Treatment of Ldlr −/− mice with NBI-74330 , a CXCR3 antagonist, markedly increased the content of Tregs in atherosclerotic plaques but reduced effector T cells in lymph nodes draining the aortic arch, thus attenuating atherosclerotic lesion formation in these mice (van Wanrooij et al 2008).…”

Chemokines in Vascular Dysfunction and Remodeling

“…65,111 MCP-1 is upregulated in the vessel wall of hypertensive animals by angiotensin II and mechanical stress. [112][113][114][115][116] In CCR2-deficient mice, hypertension-induced macrophage infiltration and vascular hypertrophy are significantly reduced. Similarly, mice with CCR2-deficient leukocytes display a blunted response to angiotensin II regarding vascular inflammation and aortic wall thickening 117,118 (Table 1).…”