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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, vol. 60, no. 5, pp. 1207-1212, doi: 10.1161/HYPERTENSIONAHA.112.201251.

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Title Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice
Author(s) Chan, Christopher T.
Moore, Jeffrey P.
Budzyn, Klaudia
Guida, Elizabeth
Diep, Henry
Vinh, Antony
Jones, Emma S.
Widdop, Robert E.
Armitage, James A.ORCID iD for Armitage, James A. orcid.org/0000-0002-3762-0911
Sakkal, Samy
Ricardo, Sharon D.
Sobey, Christopher G.
Drummond, Grant R.
Journal name Hypertension
Volume number 60
Issue number 5
Start page 1207
End page 1212
Total pages 6
Publisher Lippincott Williams & Wilkins
Place of publication Philadelphia, Pa.
Publication date 2012-11
ISSN 1524-4563
0194-911X
Keyword(s) hypertension
chemokine receptors
CCR2 antagonist
macrophages
Summary 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.
Language eng
DOI 10.1161/HYPERTENSIONAHA.112.201251
Field of Research 110201 Cardiology (incl Cardiovascular Diseases)
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1.1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30050741

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.