High dosage of simvastatin reduces TNF-alpha-induced apoptosis of endothelial progenitor cells but fails to prevent apoptosis induced by IL-1beta in vitro

Abstract

Endothelial progenitor cells (EPC) could provide a possible source for the improvement of neovascularization in injured tissues following multiple trauma. Recently, it became obvious that at least two types of EPC can be cultured from peripheral blood mononuclear cells. In this work we focused on the fraction of the easily accessible early EPC, which can be generated in clinically relevant amounts within 5 days. Periods of hyper-inflammation, systemic or local, often occur during a multiple trauma. Thus, this study was conducted to elucidate the influence of the prototypical proinflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha) on the survival of early EPC. In the past years it was observed that HMG-CoA reductase inhibitors (statins) exert protective effects during inflammatory processes. Therefore, the effect of a preconditioning of early EPC with simvastatin on the survival of EPC under proinflammatory conditions was tested as well. Incubation with 50 mu/mL TNF-alpha [0.45 ng/mL] or IL-1beta [0.25 ng/mL] resulted in a 3-fold (18.4 +/- 2.9%), respectively, 4-fold (25.5 +/- 3.4%) increase of apoptotic EPC in comparison to the untreated control (6.1 +/- 1.6%). In accordance, 24 h after the cytokines had been added, the EPC number per high power field decreased significantly. A preconditioning with simvastatin [25 microM] resulted in significant inhibition of the TNF-alpha-induced apoptosis, whereas the IL-1beta-mediated apoptosis was only slightly reduced. In conclusion, this study shows clearly that TNF-alpha and IL-1beta are harmful to early EPC and that the HMG-CoA reductase inhibitor simvastatin protects EPC from TNF-alpha- and eventually from IL-1beta-mediated apoptosis. These results suggest that simvastatin has protective effects on EPC survival and differentiation in a hyperinflammatory situation.