Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells

Abstract

Background-Cultivation of endothelial progenitor cells (EPCs) leads to premature replicative senescence, limiting ex vivo expansion for potential clinical cell therapy. Recent studies have linked senescence to the dysfunction of telomeres, the "ends" of chromosomes, via the so-called mitotic clock or culture-induced stress. The purpose of this study was to elucidate a possible role of telomere biology in the functional augmentation of EPCs by statins. Methods and Results-Human EPCs were isolated from peripheral blood. Using flow cytometry after fluorescence in situ hybridization with a telomere-specific (C 3 TA 2 ) 3 peptide nucleic acid probe (Flow-FISH), we found mean telomere length in untreated EPCs from healthy subjects to range between 8.5Ϯ0.2 and 11.1Ϯ0.5 kb with no change over 6 days of culture, excluding telomere erosion as one cause for premature senescence. Although mean telomere length did not differ between statin-treated and untreated EPCs, atorvastatin (0.1 mol/L) and mevastatin (1.0 mol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein TRF2 (telomere repeat-binding factor), as shown by immunoblotting, whereas quantitative reverse transcription-polymerase chain reaction demonstrated no increase in TRF2 mRNA. Telomere dysfunction of EPCs was also paralleled by a 4-fold increase in the DNA damage checkpoint-kinase 2 (Chk2). Conversely, statin cotreatment or overexpression of TRF2 completely suppressed Chk2 induction. Finally, overexpression of a dominant negative mutant of the TRF2 protein abrogated statin-induced enhancement of migratory activity down to baseline values. Conclusions-Ex vivo culturing of EPCs leads to "uncapping" of telomeres, indicated by the loss of TRF2. Statin cotreatment of EPCs prevents impairment of their functional capacity by a TRF2-dependent, posttranscriptional mechanism. This is the first time a beneficial effect of statins on telomere biology has been described.

White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria

“…Moreover, most of our patients have been treated with medications like statins and ACE inhibitors/ARBs, all of which possess antiinflammatory and antioxidant properties (30 -34). To the best of our knowledge, no data exist to suggest an effect of ACE inhibitors/ARBs on TRF length, while clinical and experimental data suggest that treatment with statins may have a protective effect on TRF attrition in human progenitor endothelial cells (35).…”

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

“…103 Interestingly, statins also reduce senescence and stimulate proliferation of PB-EPCs by regulating the activity of telomerase and cell cycle genes. 89,104 Thus the therapeutic potential of endothelial progenitor cells could potentially be enhanced by noninvasive pharmacological manipulation and used to accelerate re-endothelialization of injured vessels and inhibit neointimal hyperplasia after revascularization procedures.…”

Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy current status and future developments

“…Pretreatment of endothelial progenitor cells with statins, eNOSoverexpression of PPAR-gamma agonists before transfer increases their migratory, invasive, and neovascularization capacity -effects that are mediated by activation of endothelial nitric oxide synthase (Shao et al 2008;Spyridopoulos et al 2004). Similary, own results showed that prestimulation of endothelial progenitor cells from diabetic individuals with the peroxisome proliferator activated receptor -agonist rosiglitazone, enhances nitric oxide availability and the in vivo endothelial repair capacity of these cells (Sorrentino et al 2007).…”