Abstract 2046: The PPAR-γ Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients with Coronary Artery Disease and Normal Glucose Tolerance
Background: PPAR-γ 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 in a prospective, randomized, double-blind study on patients with documented stable coronary artery disease and normal glucose tolerance.
Methods and 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. Mechanistic experiments in cultured human EPC showed expression of PPARγ. TZD increased cultured EPC numbers and migration and reduced NADPH-oxidase mediated superoxide release. The TZD effect was reversed by the PPARγ inhibitor GW9662 and mimicked by treatment with adiponectin. The increase of EPC numbers was related to the prevention of apoptotic cell death mediated by PI3 kinase and upregulation of telomere repeat-binding factor 2.
Conclusions: The PPAR-γ agonist pioglitazone increases the number and function of endothelial progenitor cells in patients with coronary artery disease. The effect represents a potential regenerative mechanism and is observed in normoglycemic individuals with stable coronary artery disease.