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

Full text for this resource is not available from the Research Repository.

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)

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.

Dimensions Badge

Altmetric Badge

Item type Article
URI https://vuir.vu.edu.au/id/eprint/23646
DOI 10.1161/HYPERTENSIONAHA.112.201251
Official URL http://hyper.ahajournals.org/content/60/5/1207
Subjects Historical > FOR Classification > 1102 Cardiorespiratory Medicine and Haematology
Current > Division/Research > College of Health and Biomedicine
Keywords ResPubID26529, hypertension, chemokine receptors, CCR2 antagonist, macrophages
Citations in Scopus 86 - View on Scopus
Download/View statistics View download statistics for this item

Search Google Scholar

Repository staff login