The peroxisome proliferator-activated receptor-gamma agonist pioglitazone increases number and function of endothelial progenitor cells in patients with coronary artery disease and normal glucose tolerance.
OBJECTIVE
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) 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.


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 microg/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 gamma antagonist GW9662 and mimicked by treatment with adiponectin.


CONCLUSIONS
The PPAR gamma 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.
Werner
Christian
C
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany.
Kamani
Christel Hermann
CH
Gensch
Christoph
C
Böhm
Michael
M
Laufs
Ulrich
U
D052242:Adiponectin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D010919:Placebos; D011446:Prospective Studies; D012016:Reference Values; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D045162:Thiazolidinediones / Q000627:therapeutic use*
D052242:Adiponectin; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010919:Placebos; D045162:Thiazolidinediones; D002097:C-Reactive Protein; D000077205:Pioglitazone