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p38 Mitogen-Activated Protein Kinase Downregulates Endothelial Progenitor Cells

Background—Transplantation of endothelial progenitor cells (EPCs) improves neovascularization after ischemia, but patients with coronary artery disease (CAD) or diabetes mellitus show a reduced number of EPCs and impaired functional activity. Therefore, we investigated the effects of risk factors, such as glucose and TNF-&agr;, on the number of EPCs in vitro to elucidate the underlying mechanisms. Methods and Results—EPCs of patients or healthy subjects were isolated from peripheral blood. Incubation with glucose or TNF-&agr; dose-dependently reduced the number of EPCs (79.9±1.3% and 74.3±8.1% of control; P<0.05, respectively). This reduction was not caused by apoptosis. TNF-&agr; and glucose induced a dose- and time-dependent activation of the p38 MAP kinase, the downstream kinase mitogen- and stress-activated kinase 1, and the transcription factor cAMP-responsive element–binding protein (CREB), in EPCs. Moreover, EPCs from CAD patients had significantly higher basal p38-phosphorylation levels (1.83±0.2-fold increase; P<0.05) compared with healthy subjects. The inhibition of the p38-kinase by SB203580 or infection with a dominant negative p38 kinase adenovirus significantly increased basal number of EPCs (136.7±6.3% and 142.9±18% versus control, respectively). Likewise, ex vivo cultivation of EPCs from patients with CAD with SB203580 significantly increased the number of EPCs and partially reversed the impaired capacity for neovascularization of EPCs in vivo (relative blood flow: 0.40±0.03 versus 0.64±0.08, P<0.05). The increased numbers of EPCs by SB203580 were associated with an augmentation of EPC proliferation and a reduction of cells expressing the monocytic marker proteins CD14 and CD64, suggesting that p38 regulates proliferation and differentiation events. Conclusions—These results demonstrate that p38 MAP kinase plays a pivotal role in the signal transduction pathways regulating the number of EPCs ex vivo. SB203580 can prevent the negative effects of TNF-&agr; and glucose on the number of EPCs and may be useful to improve the number of EPCs for potential cell therapy.