Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-γ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1α levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS−/− and iNOS−/− mice. Male C57BL/6 wild-type (WT), eNOS−/−, and iNOS−/− mice received 10 mg·kg−1·day−1 Pio (Pio+) or water alone (Pio−) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 ± 1.4% vs. 39.0 ± 1.1%; P < 0.001), as well as in the eNOS−/− (32.0 ± 1.6% vs. 44.2 ± 1.9%; P < 0.001) and iNOS−/− (18.0 ± 1.2% vs. 45.5 ± 2.3%; P < 0.001) mice. The protective effect of Pio in eN...