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The Peroxisome Proliferator–Activated Receptor- Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients With Coronary Artery Disease and Normal Glucose Tolerance

From the Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany

Address correspondence and reprint requests to Ulrich Laufs, Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany. E-mail: ulrich{at}laufs.com

Abbreviations: CFU, colony-forming unit; CRP, C-reactive protein; DiLDL, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine–labeled acetylated LDL; EBM, endothelial cell basal medium; FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; HOMA, homeostasis model assessment; hsCRP, high-sensitivity CRP; KDR, kinase insert domain receptor; MNC, mononuclear cell; PE, phycoerythrin; PMA, phorbol myristate acetate; PPAR, peroxisome proliferator–activated receptor; TZD, thiazolidinedione

OBJECTIVE—Peroxisome proliferator–activated receptor- (PPAR) agonists (thiazolidinediones [TZDs]) are used for the treatment of diabetes. Bone marrow–derived endothelial progenitor cells (EPCs) improve vascular function and predict cardiovascular risk. The effect of pioglitazone therapy on EPCs was examined.

RESEARCH DESIGN AND METHODS AND RESULTS—We performed a prospective, randomized, double-blind study on patients with documented stable coronary artery disease and normal glucose tolerance. Of 54 patients with normal fasting glucose levels, 18 showed impaired glucose tolerance and 36 patients with normal glucose tolerance were randomized to 30-day treatment with pioglitazone (45 mg) or placebo in addition to optimal medical therapy. All patients in the TZD group showed an increase of adiponectin levels as an indicator of compliance (11.4 ± 1.1 to 36.8 ± 2.1 µg/ml; P < 0.001). TZD, but not placebo, decreased mean high-sensitivity C-reactive protein to 43 ± 19% (P < 0.05). Pioglitazone increased CD34⁺/kinase insert domain receptor⁺ EPCs to 142 ± 9% and cultured 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine–labeled acetylated LDL⁺/lectin⁺ EPCs to 180 ± 3% (P < 0.05). EPC numbers were not changed in the placebo group. TZD increased the SDF-1–induced migratory capacity to 146 ± 9% per EPC number (P < 0.05) and upregulated the clonogenic potential of EPCs, increasing the colony-forming units to 172 ± 12% (P < 0.001). In cultured human EPCs, TZD increased EPC numbers and migration and reduced NADPH-oxidase activity. The TZD effect was reversed by the PPAR antagonist GW9662 and mimicked by treatment with adiponectin.

CONCLUSIONS—The PPAR agonist pioglitazone increases the number and function of EPCs in patients with coronary artery disease. The effect represents a potential regenerative mechanism in atherosclerosis and is observed in normoglycemic individuals with stable coronary artery disease.

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