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

• Published in: Basic research in cardiology 2010-05, Vol.105 (3), p.389-397
• Main Authors: Seeger, Florian H., Sedding, Daniel, Langheinrich, Alexander C., Haendeler, Judith, Zeiher, Andreas M., Dimmeler, Stefanie
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atherosclerosis - etiology; Atherosclerosis - prevention & control; Cardiology; Disease Models, Animal; Disease Progression; Enzyme Inhibitors - pharmacology; Hypercholesterolemia - complications; Imidazoles - pharmacology; Medicine; Medicine & Public Health; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - physiology; Mice; Mice, Knockout; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Original Contribution; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Phosphorylation - physiology; Pyridines - pharmacology
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-009-0072-9

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 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