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Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice

Chan, Christopher T, Moore, Jeffrey P, Budzyn, Klaudia, Guida, Elizabeth, Diep, Henry, Vinh, Antony, Jones, Emma S, Widdop, Robert E, Armitage, James A, Sakkal, Samy, Ricardo, Sharon D, Sobey, Christopher G and Drummond, Grant R (2012) Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension: Journal of the American Heart Association, 60 (5). pp. 1207-1212. ISSN 0194-911X (print), 1524-4563 (online)

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Infiltration of macrophages into the artery wall plays detrimental roles during hypertension by promoting vascular inflammation and endothelial dysfunction, and it occurs via a chemo-attractant action of chemokines on macrophage cytokine receptors. We sought to identify the key chemokine receptors associated with macrophage infiltration into 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 leukocyte accumulation. Mice treated with DOCA/salt for 21 days displayed markedly elevated systolic blood pressure (158±2 versus 114±5 mm Hg in sham group; P<0.0001). Polymerase chain reaction screening via a gene array of 20 chemokine receptors indicated an increased expression of CCR2 in aortas of DOCA/salt-treated mice. Real-time polymerase chain reaction confirmed mRNA upregulation of CCR2 in aortas from DOCA/salt-treated animals and of the CCR2 ligands CCL2, CCL7, CCL8, and CCL12 (all >2-fold versus sham; P<0.05). Flow cytometry revealed 2.9-fold higher macrophage numbers (ie, CD45+ CD11b+ F4/80+ cells) in the aortic wall of DOCA/salt versus sham-treated mice. Intervention with a CCR2 antagonist, INCB3344 (30 mg/kg per day, IP), 10 days after the induction of hypertension with DOCA/salt treatment, reduced the aortic expression of CCR2 mRNA and completely reversed the DOCA/salt-induced influx of macrophages. Importantly, INCB3344 substantially reduced the elevated blood pressure in DOCA/salt-treated mice. Hence, our findings highlight CCR2 as a promising therapeutic target to reduce both macrophage accumulation in the vascular wall and blood pressure in hypertension.

Item Type: Article
Uncontrolled Keywords: ResPubID26529, hypertension, chemokine receptors, CCR2 antagonist, macrophages
Subjects: Current > FOR Classification > 1102 Cardiorespiratory Medicine and Haematology
Current > Division/Research > College of Health and Biomedicine
Depositing User: Ms Phung.T Tran
Date Deposited: 22 Dec 2013 23:31
Last Modified: 28 Feb 2020 04:52
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Citations in Scopus: 65 - View on Scopus

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