A CCR2/CCR5 antagonist attenuates an increase in angiotensin II-induced CD11b+ monocytes from atherogenic ApoE-/- mice.
OBJECTIVE
Monocyte infiltration into the vessel wall, a process primarily mediated by the interaction between monocyte chemoattractant protein-1 (MCP-1) and its receptor, CCR2, is a key step in atherogenesis. Angiotensin II (Ang II) enhances this monocyte infiltration by increasing the endothelial binding integrin, CD11b. However, the modulation of the Ang II-induced CD11b expression in monocytes in not clear. The aim of this study was to determine if MCP-1/MCP-2 receptor (CCR2) interaction regulates monocyte CD11b expression after 7 days of Ang II infusion.


RESULTS
In ApoE(-/-) mice continuous subcutaneous infusion of Ang II (0.75 mg/kg/day) for 7 days significantly increased CD11b expression in circulating monocytes as measured by flow cytometry. CD11b expression in ApoE(-/-) was increased from 135 +/- 9 to 176 +/- 12 mean fluorescent intensity (MFI), control and Ang II-treated, respectively while in C57B/J wildtype mice CD11b increased from 128 +/- 13 to 174 +/- 8 MFI, control and Ang II-treated, respectively. Interestingly, co-infusion of either MCP-1 neutralizing antibody (25 microg/kg/day) or a CCR2 antagonist (500 microg/kg/day) with Ang II for 7 days effectively inhibited monocyte CD11b expression and this inhibition was accompanied by a down-regulated vascular infiltration of Mac-2 positive monocyte-derived macrophages.


CONCLUSIONS
Our data in the atherogenic ApoE(-/-) mouse demonstrates that the Ang II induced increase in both monocytic CD11b integrin expression and monocyte vascular infiltration occurs early in atherogenesis. These Ang II-induced monocytic changes are in part regulated through the MCP-1/CCR2 interaction.
Major
Terry C
TC
Cardiovascular and Atherosclerosis Biology, Pfizer Global Research and Development, Ann Arbor, MI, USA. tcmajor@umich.edu
Olszewski
Bronia
B
Rosebury-Smith
Wendy S
WS
D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D065100:CCR5 Receptor Antagonists; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D051381:Rats; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001057:Apolipoproteins E; D065100:CCR5 Receptor Antagonists; D039481:CD11b Antigen; D054390:Receptors, CCR2; D000804:Angiotensin II