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

Chan, Christopher T and Moore, Jeffrey P and Budzyn, Klaudia and Guida, Elizabeth and Diep, Henry and Vinh, Antony and Jones, Emma S and Widdop, Robert E and Armitage, James A and Sakkal, Samy and Ricardo, Sharon D and 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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Abstract

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: FOR Classification > 1102 Cardiovascular Medicine and Haematology
Faculty/School/Research Centre/Department > College of Health and Biomedicine
Depositing User: Ms Phung.T Tran
Date Deposited: 22 Dec 2013 23:31
Last Modified: 23 Sep 2014 00:27
URI: http://vuir.vu.edu.au/id/eprint/23646
DOI: 10.1161/HYPERTENSIONAHA.112.201251
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Citations in Scopus: 6 - View on Scopus

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