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Diabetes Publish Ahead of Print published online ahead of print July 10, 2007
DOI: 10.2337/db07-0069
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Original Research

The PPAR-{gamma} Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients with Coronary Artery Disease and Normal Glucose Tolerance

Christian Werner, Christel Hermann Kamani, Christoph Gensch, Michael Böhm, and Ulrich Laufs

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar; Germany

Correspondence: ulrich{at}laufs.com

Key Words: endothelial progenitor cells • thiazolidinediones • coronary artery disease • PPAR-{gamma} • glucose tolerance

Objective:PPAR-{gamma} agonists (thiazolidinediones, TZDs) are used for the treatment of diabetes mellitus. Bone marrow-derived endothelial progenitor cells (EPC) improve vascular function and predict cardiovascular risk. The effect of pioglitazone therapy on EPC was examined.

Research Design and Methods:Prospective, randomized, double-blind study on patients with documented stable coronary artery disease and normal glucose tolerance.

Results:Out 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 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 CRP to 43±19%, p<0.05. Pioglitazone increased CD34+/KDR+ EPC to 142±9% as well as cultured DiLDL/Lectin-positive EPC 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 EPC increasing the colony forming units to 172±12%, p<0.001. In cultured human EPC, TZD increased EPC numbers and migration and reduced NADPH-oxidase activity. The TZD effect was reversed by the PPAR{gamma} antagonist GW9662 and mimicked by treatment with adiponectin.

Conclusions:The PPAR-{gamma} agonist pioglitazone increases the number and function of endothelial progenitor cells 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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