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Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression

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Abstract

Initial trials suggest that bone marrow-derived vasculogenic cells augment neovascularization in patients after myocardial infarction. Moreover, in some experimental settings, they also provide an anti-atherosclerotic effect by maintaining the integrity of the endothelium. Risk factors for coronary artery disease were shown to reduce the number and functional activity of vasculogenic cells and increased cellular p38 MAP kinase activity. Inhibition of p38 MAP kinase increases the number and functional activity of pro-angiogenic cells in vitro and clinical trials are under way to examine the effect of p38 inhibition in patients with CAD. Here, we examined the effect of systemic p38 MAP kinase inhibition on vasculogenic cells and atherosclerotic disease progression in vivo. Treatment of ApoE−/− mice with the p38 inhibitor SB203580 significantly increased the number of pro-angiogenic cells such as Sca-1+Flk-1+ as well as CD11blowFlk-1+ cells and reduced the number of the inflammatory Gr1+CD45+ cells. Moreover, invasion capacity of bone marrow-derived mononuclear cells under basal conditions as well as towards a gradient of SDF-1 was significantly augmented in ApoE−/− mice after p38 inhibition. Finally, treatment of ApoE−/− mice with SB203580 for 4 months reduced atheromatous lesion size by 51 ± 3% (p < 0.05) without affecting the density of vasa vasorum in the plaques. In conclusion, this study demonstrates that systemic p38 MAP kinase inhibition with SB203580 improves the number and function of vasculogenic cells in an animal model of hypercholesterolemia, and reduces atherosclerotic disease progression in ApoE−/− mice.

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Acknowledgments

We gratefully thank Tina Rasper, Ariane Fischer and Tino Röxe for expert technical assistance as well as Laura Ehmke for animal care. This work was supported by a start-up-grant of the University of Frankfurt (FHS) and the Excellence Cluster Cardio Pulmonary Syndrome (ECCPS) by the DFG (Exc 147/1).

Conflict of interest statement

Stefanie Dimmeler received a research grant from GSK. All other authors have no disclosures.

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Author notes

  1. Judith Haendeler

    Present address: Molecular Cell & Aging Research, IUF (Institute for Preventive Medicine) at the University of Duesseldorf gGmbH, Düsseldorf, Germany

Authors and Affiliations

  1. Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Universität Frankfurt, Haus 25, 4. Stock, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Florian H. Seeger & Stefanie Dimmeler

  2. Department of Cardiology, Internal Medicine III, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Florian H. Seeger & Andreas M. Zeiher

  3. Department of Internal Medicine/Cardiology, University of Giessen and Marburg GmbH, Giessen, Germany

    Daniel Sedding

  4. Department of Diagnostic Radiology, University of Giessen & Marburg GmbH, Giessen, Germany

    Alexander C. Langheinrich

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  1. Florian H. Seeger
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  2. Daniel Sedding
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  4. Judith Haendeler
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Correspondence to Stefanie Dimmeler.

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F. H. Seeger and D. Sedding contributed equally to this manuscript.

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Seeger, F.H., Sedding, D., Langheinrich, A.C. et al. Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression. Basic Res Cardiol 105, 389–397 (2010). https://doi.org/10.1007/s00395-009-0072-9

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