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

作者：Ye Yumei; Lin Yu; Manickavasagam Saraswathy; Perez Polo J Regino; Tieu Brian C; Birnbaum Yochai^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2008, 295(6): H2436-H2446.

DOI：10.1152/ajpheart.00690.2008

• endothelial nitric oxide synthase
• inducible nitric oxide synthase
• peroxisome proliferator-activated receptor-gamma

Pioglitazone 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 A(2) (cPLA(2)), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF(1 alpha) 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 eNOS(-/-) mice was smaller than in the WT (P < 0.001) and iNOS(-/-) (P < 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS(-/-) mice. iNOS was undetectable in all six groups. Pio increased cPLA(2), COX2, and PGI(2) synthase levels in the WT, as well as in the eNOS(-/-) and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF(1 alpha) levels and cPLA(2) and COX2 activity in the WT, eNOS(-/-), and iNOS(-/-) mice. In conclusion, the myocardial protective effect of Pio 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.

• 出版日期2008-12