Abstract 3694: P38-MAP-Kinase-inhibition Changes Balance From Inflammation Towards Vascular Repair In Metabolic Syndrome
Initial trials suggest that bone marrow-derived mononuclear cells (BMC) augment neovascularization in patients after MI. However, patients with cardiovascular risk factors show reduced number and impaired functional activity of endothelial progenitor cells (EPC). We recently demonstrated that ex vivo treatment with a p38 MAPK-inhibitor can reverse these effects. As there are no data regarding to p38-inhibition in vivo, the aim of this study was to examine whether p38-inhibition can reverse the metabolic syndrome associated dysfunction of progenitor cells in a mouse model. At an age of 12 weeks, Leptinreceptor ko mice (db mice) exhibited typical features of metabolic syndrome. In peripheral blood, db mice showed a sig. lower number of EPC (sca-1+/flk-1+ cells) and an increased number of inflammatory cells (Gr-1+/CD45+ cells) compared to their wt littermates (0.05±0.07% vs. 1.6±1.1% and 48.2±11% vs. 23.4±5.9%, respectively). Treatment of db mice with the p38-inhibitor SB203580 (10 mg/kg bw ip, 4 days) sig. increased the number of sca-1+/flk-1+ cells (29±7 -fold increase) and lowered the number of Gr-1+/CD45+ cells (69±11% of db mice). Moreover, EPC derived from db mice demonstrated sig. reduced colony forming activity (CFU) (60±6 % of wt), and BMC showed an impaired invasion capacity (58±13% of wt). P38-inhibition significantly improved CFU (179±63% of wt) and BMC invasion capacity (119±75% of wt). To further investigate the underlying mechanisms, we assessed the DNA binding activity of transcription factors in BMC. Isoforms of Stat and Pax transcription factors, which are known to regulate inflammation and myeloid commitment, were increased in db mice. P38-inhibitor treatment reduced the increased DNA binding activity (Stat3 47±9%, Stat5 80±9%, Stat6 85±28, Pax5 69±19% of db mice w/o p38-treatment) This study provides first evidence that p38-inhibition improves the impaired EPC number and function in metabolic syndrome. In addition, the inflammatory response was significantly suppressed indicating that p38-inhibition changes the balance from inflammation towards vascular repair. Dysregulation of transcription factors regulating myeloid versus endothelial commitment may contribute to the observed protective activity of p38-inhibition.