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A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice

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Abstract

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.

Methods and 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 μg/kg/day) or a CCR2 antagonist (500 μg/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.

Conclusion

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.

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Conflict of interest

The affiliation of all authors to the sponsor, Pfizer, Inc., is that all authors were former employees of Pfizer and now have either retired or are in new research positions. No conflict of interest has existed or exists now for this submitted work by any of the authors.

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Author notes

  1. Wendy S. Rosebury-Smith

    Present address: Cutting Image Histology, LLC, Ann Arbor, MI, USA

Authors and Affiliations

  1. Cardiovascular and Atherosclerosis Biology, Pfizer Global Research and Development, Ann Arbor, MI, USA

    Terry C. Major & Bronia Olszewski

  2. Department of Surgery, University of Michigan Health System, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA

    Terry C. Major

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  1. Terry C. Major
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Correspondence to Terry C. Major.

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Major, T.C., Olszewski, B. & Rosebury-Smith, W.S. A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b+ Monocytes from Atherogenic ApoE−/− Mice. Cardiovasc Drugs Ther 23, 113–120 (2009). https://doi.org/10.1007/s10557-008-6157-0

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