Abstract 3215: Anti-Diabetic Drug Pioglitazone Protects the Heart Via Activation of PPAR-γ, PI3 Kinase , Akt and eNOS Pathway in a Rabbit Model of Myocardial Infarction
Background: The insulin-sensitizing drug pioglitazone, a ligand for peroxisome proliferator activated receptor-γ (PPAR-γ), has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear.
Methods: Rabbits underwent 30 min of coronary occlusion followed by 48h of reperfusion. Rabbits were assigned randomly to 9 groups (n=10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1mg/kg/day pioglitazone), pioglitazone+5HD group (fed the pioglitazone diet + i.v. 5mg/kg 5-hydroxydecanoate, a mitochondrial KATP channel blocker), pioglitazone+GW9662 group (fed the pioglitazone diet + i.v. 2mg/kg GW9662, a PPAR-γ antagonist), GW9662 group (fed a normal diet + i.v. GW9662), and pioglitazone+wortmannin group (fed the pioglitazone diet + i.v. 0.6mg/kg wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor), wortmannin group (fed a normal diet + i.v. wortmannin), pioglitazone+L-NAME group (fed the pioglitazone diet + i.v. 10mg/kg L-NAME, a NOS inhibitor), L-NAME group (fed a normal diet + i.v. L-NAME). All group fed the diets for 7 days. The risk area and non-risk area of the left ventricle (LV) were separated by Evans blue dye and the infarct area was determined by TTC staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt, phospho-eNOS in the myocardium following reperfusion.
Results: The infarct size was significantly smaller in the pioglitazone group (21±2%) than in the control group (43±3%). This effect was abolished by GW9662 (42±3%), wortmannin (40±3%) or L-NAME (42±7%) but not by 5-HD (24±5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group.
Conclusions: Pioglitazone reduces the myocardial infarct size via activation of PPAR-γ, PI3K, Akt and eNOS pathway, but not via opening the mitochondrial KATP channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease because pioglitazone does not affect the mitochondrial KATP channels, regardleess of the use of sufonylureas that affect mitochondrial KATP channels.