Basic Research in Cardiology

, Volume 105, Issue 3, pp 389–397

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

  • Florian H. Seeger
  • Daniel Sedding
  • Alexander C. Langheinrich
  • Judith Haendeler
  • Andreas M. Zeiher
  • Stefanie Dimmeler
Original Contribution

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.

Keywords

Pro-angiogenic cells EPC Atherosclerosis ApoE−/− mice SB203580 Vasculogenic cells 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Florian H. Seeger
    • 1
    • 2
  • Daniel Sedding
    • 3
  • Alexander C. Langheinrich
    • 4
  • Judith Haendeler
    • 5
  • Andreas M. Zeiher
    • 2
  • Stefanie Dimmeler
    • 1
  1. 1.Institute for Cardiovascular Regeneration, Centre of Molecular MedicineUniversität FrankfurtFrankfurtGermany
  2. 2.Department of CardiologyInternal Medicine III, Goethe UniversityFrankfurtGermany
  3. 3.Department of Internal Medicine/CardiologyUniversity of Giessen and Marburg GmbHGiessenGermany
  4. 4.Department of Diagnostic RadiologyUniversity of Giessen & Marburg GmbHGiessenGermany
  5. 5.Molecular Cell & Aging ResearchIUF (Institute for Preventive Medicine) at the University of Duesseldorf gGmbHDüsseldorfGermany

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