Abstract 17173: Reversal of Vascular Macrophage Accumulation and Hypertension by a Chemokine C-C motif Receptor 2 Antagonist in Deoxycorticosterone/Salt-Treated Mice
Macrophage infiltration into the artery wall plays a pathophysiological role in hypertension by promoting vascular inflammation and endothelial dysfunction. Chemokines are chemoattractant cytokines that bind to receptors on leukocytes and promote their migration into tissues. In this study we sought to identify chemokine receptors that are upregulated in the vascular wall during deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice, and to evaluate the impact of pharmacological inhibition of these receptors on blood pressure and macrophage accumulation. Mice treated with DOCA/salt for 21 d displayed markedly elevated systolic blood pressures (158±2 mmHg vs 114±5 mmHg in sham group; P<0.05, n≥13). PCR screening via a gene array containing 20 different chemokine receptors indicated an increase in expression of chemokine C-C motif receptor 2 (CCR2) in aortas of DOCA/salt-treated mice. Real-time PCR confirmed upregulation of CCR2 in aortas from DOCA/salt-treated animals, and also levels of the CCR2 ligands CCL2, CCL7, CCL8 and CCL12 (>2-fold versus sham for all genes; P<0.05, n=7). Flow cytometric analysis revealed a 2.9-fold increase in macrophages (i.e. CD45+CD11b+ F4/80+ cells)in the aortic wall of DOCA/salt- versus sham-treated mice (P<0.05, n=5). Intervention with a CCR2 antagonist, INCB3344 (30 mg/kg/d, i.p.), ten days after the induction of hypertension with DOCA/salt treatment, reduced elevated aortic expression of CCR2 by 55% (P<0.05, n≥6) and completely reversed the DOCA/salt-induced influx of macrophages (P<0.05, n=5). Importantly, INCB3344 reduced the elevated blood pressure in DOCA/salt-treated mice by 45% (P<0.05, n≥10). Hence, our findings highlight CCR2 as a promising therapeutic target to reduce both macrophage accumulation in the vascular wall and BP in hypertension.
- © 2012 by American Heart Association, Inc.