Abstract 2969: Inhibition of the P38 Map Kinase in vivo Improves Number and Functional Activity of Proangiogenic Cells and Reduces Atherosclerotic Disease Progression
Initial trials suggest that vasculogenic cells including bone marrow-derived mononuclear cells (BMC), CD34+ endothelial progenitor cells or ex vivo expanded pro-angiogenic myeloid cells augment neovascularization in patients after myocardial infarction. However, patients with cardiovascular risk factors show reduced number and impaired functional activity of vasculogenic cells and increased activity of the p38 MAP kinase. Therefore, we examined the effect of p38 MAP kinase inhibition on vasculogenic cells in an in vivo model of metabolic syndrome and atherosclerosis. Consistent with the impairment of vasculogenic cells by risk factors for CAD in humans, Leprdb mice exhibited a significantly lower number of Sca-1+/Flk-1+ cells whereas the number of Gr1+/CD45+ inflammatory cells was increased 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, the reduced number of pro-angiogenic cell clusters (60±6 % of wt) and impaired BMC invasion capacity (58±13% of wt) were significantly augmented in Leprdb mice after p38 inhibition. Moreover, we confirmed that SB203580 in vivo treatment profoundly suppressed p38 phosphorylation and the phosphorylation of CREB, which is an established p38 downstream target, in immunoblots. Likewise, in SB203580 treated ApoE−/− mice the number of proangiogenic cells measured as Sca-1+/Flk-1+ as well as CD11blow/Flk-1+ cells was significantly increased. Finally, treatment of ApoE−/− mice with SB203580 for 4 months reduced atheromatous lesion size by 51±3% (p<0.05). This study demonstrates that systemic p38 MAP kinase inhibition with SB203580 improves the number and function of vasculogenic cells in animal models of metabolic syndrome and hypercholes-terolemia, and reduces atherosclerotic disease progression in ApoE−/− mice.