The PPAR-gamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells.
PPAR-gamma agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235+/-60%) and the bone marrow (166+/-30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231+/-21% (n=24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246+/-73% and increased expression of telomere repeat-binding factor 2 by 320+/-50%. In vivo neoangiogenesis was increased two-fold (214+/-42%, 20 days). The NOS inhibitor L-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65+/-2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H(2)O(2)-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases.
Gensch
Christoph
C
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany.
Clever
Yvonne P
YP
Werner
Christian
C
Hanhoun
Milad
M
Böhm
Michael
M
Laufs
Ulrich
U
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D000077205:Pioglitazone; D013234:Stem Cells / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D000077205:Pioglitazone