Inhibition of the p38 MAP kinase in vivo improves number  and functional activity of vasculogenic cells and reduces  atherosclerotic disease progression.
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 proangiogenic 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 CD11b(low)Flk-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.
Seeger
Florian H
FH
Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Universität Frankfurt, Frankfurt, Germany.
Sedding
Daniel
D
Langheinrich
Alexander C
AC
Haendeler
Judith
J
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580