Abstract 3461: Inhibition of the p38 MAP Kinase in Vivo Improves Number and Functional Activity of Progenitor Cells and Reduces Atherosclerotic Disease Progression
Initial trials suggest that bone marrow-derived mononuclear cells (BMC) and ex vivo expanded endothelial progenitor cells (EPC) augment neovascularisation in patients after myocardial infarction. However, patients with cardiovascular risk factors show reduced number and impaired functional activity of EPC and increased activity of the p38 MAP kinase. Therefore, we examined the effect of p38 MAP kinase inhibition on progenitor cells in an in vivo model of metabolic syndrome and atherosclerosis. Consistent with the impairment of EPC by risk factors for coronary artery disease in humans, Leprdb mice exhibited a significantly lower number of EPC (sca-1+/flk-1+ cells) and an increased number of inflammatory cells (Gr1+/CD45+ cells) compared to their wild type littermates (0.05±0.07% vs. 1.6±1.1%, and 48.2±11% vs. 23.4±5.9%, respectively). Treatment of Leprdb mice with the p38 inhibitor SB203580 significantly increased the number of sca-1+/flk-1+ cells (29±7 -fold increase) and lowered the number of GR1+/CD45+ cells (69±11% of Leprdb mice). Moreover, both, reduced EPC colony forming activity (60±6 % of wt), and impaired BMC invasion capacity (58±13% of wt) were significantly improved in Leprdb mice by p38 inhibition. Finally, treatment of ApoE−/− mice with the SB203580 for 4 months reduced atheromatous lesion size by 51±3% (p<0.05). This study provides first evidence that p38 MAP kinase inhibition with SB203580 improves the impaired progenitor cell number and functional activity in an animal model of metabolic syndrome. Improvement of progenitor cell function is associated with reduction of atheroscle-rotic disease progression in ApoE−/− mice.