HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells

Abstract

Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in peripheral blood and shown to incorporate into foci of neovascularization, consistent with postnatal vasculogenesis. These circulating EPCs are derived from bone marrow and are mobilized endogenously in response to tissue ischemia or exogenously by cytokine stimulation. We show here, using a chemotaxis assay of bone marrow mononuclear cells in vitro and EPC culture assay of peripheral blood from simvastatin-treated animals in vivo, that the HMG-CoA reductase inhibitor, simvastatin, augments the circulating population of EPCs. Direct evidence that this increased pool of circulating EPCs originates from bone marrow and may enhance neovascularization was demonstrated in simvastatin-treated mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. The role of Akt signaling in mediating effects of statin on EPCs is suggested by the observation that simvastatin rapidly activates Akt protein kinase in EPCs, enhancing proliferative and migratory activities and cell survival. Furthermore, dominant negative Akt overexpression leads to functional blocking of EPC bioactivity. These findings establish that augmented mobilization of bone marrow-derived EPCs through stimulation of the Akt signaling pathway constitutes a novel function for HMG-CoA reductase inhibitors.

Oxidized Low-Density Lipoprotein Induces Apoptosis in Endothelial Progenitor Cells by Inactivating the Phosphoinositide 3-Kinase/Akt Pathway

“…Transduction of WT EPCs with Ad-myrAkt, a constitutively active Akt isoform, significantly decreased the deleterious impact of oxLDL on the p-Akt/Akt ratio and lowered oxLDL-induced EPC apoptosis. The finding that Akt activation is critical for EPC survival is consistent with the reports of Llevadot et al [21] and Lefèvre et al [18] who demonstrated enhanced Akt activation and EPC function as well as survival following EPC treatment with the HMG-CoA reductase inhibitor simvastatin or the antioxidant resveratrol, respectively.…”

Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α

“…Therefore, we used several marker combinations to quantitate circulating EPCs. In independently repeated experiments, EPCs were identified as cells double labeled with either Tie2 and VEGFR2 (32,33) or (CXC chemokine receptor 4) CXCR4 and VEGFR2 (8,15,34). Following treatment with hyperoxia, diabetic mice demonstrate a significant 5-fold increase in circulating CXCR4 + /VEGFR2 + EPCs and Tie2 + / VEGFR2 + EPCs ( Figure 2).…”

Mobilization of Circulating Endothelial Progenitor Cells Correlates with the Clinical Course of Hantavirus Disease

“…Estrogen and physical exercise elevate the number of EPCs, whereas increasing age, diabetes, and smoking are associated with the depletion of cEPCs (17)(18)(19)(20)(21). Furthermore, drugs for the treatment of cardiovascular pathologies, such as statins and angiotensin-converting enzyme (ACE) inhibitors positively modulate EPC levels, thereby improving reendothelialization (22)(23)(24). The role of EPCs in different pathological conditions with vascular alteration and their impact on the outcome have been described in many studies, and their potential use as a predictive marker and as a therapeutic approach is under investigation (25)(26)(27)(28)(29).…”