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

摘要

betaoglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. Am J Physiol Heart Circ Physiol 295: H2436-H2446, 2008. First published October 17, 2008; doi:10.1152/ajpheart.00690.2008.-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-^ agonist pioglitazone (betao) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGFia levels without activating eNOS and iNOS. We asked whether betao also limits IS in eNOS~'~ and iNOS-'- mice. Male C57BL/6 wild-type (WT), eNOS-'-, and iNOS-'- mice received 10 mg-kg'May"1 betao (betao+) or water alone (betao? 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, betao reduced IS in the WT (15.4 +- 1.4% vs. 39.0 +- 1.1%; P < 0.001), as well as in the eNOS~'- beta2.0 +- 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 betao in eNOS~'~ mice was smaller than in the WT (P < 0.001) and iNOS-'~ (P < 0.001) mice. betao increased myocardial Ser633 and Serll77 phosphorylated eNOS levels in the WT and iNOS~'~ mice. iNOS was undetectable in all six groups. betao increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS~'~ and iNOS~'~, mice. betao increased the myocardial 6-keto-PGFi?levels and cPLA2 and COX2 activity in the WT, eNOS~'~, and iNOS~'~ mice. In conclusion, the myocardial protective effect of betao is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized 1 Dollars 001N200306467Dollars 1200