title: Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice.
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.
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Chan
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Moore
authors.forename: Klaudia
authors.initials: K
authors.lastname: Budzyn
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Guida
authors.forename: Henry
authors.initials: H
authors.lastname: Diep
authors.forename: Antony
authors.initials: A
authors.lastname: Vinh
authors.forename: Emma S
authors.initials: ES
authors.lastname: Jones
authors.forename: Robert E
authors.initials: RE
authors.lastname: Widdop
authors.forename: James A
authors.initials: JA
authors.lastname: Armitage
authors.forename: Samy
authors.initials: S
authors.lastname: Sakkal
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D054410:Chemokine CCL7 / Q000235:genetics; D054412:Chemokine CCL8 / Q000235:genetics; D003900:Desoxycorticosterone; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012965:Sodium Chloride; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C491224:Ccl12 protein, mouse; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; C515454:Ccl8 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054412:Chemokine CCL8; C505875:INCB3344; D018945:Monocyte Chemoattractant Proteins; D011759:Pyrrolidines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D003900:Desoxycorticosterone; D012965:Sodium Chloride