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

Abstract

Ye Y, Lin Y, Manickavasagam S, Perez-Polo JR, Tieu BC, Birnbaum Y. 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 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 (Pio) limits IS, upregulates and activates cPLA 2 and COX2, and increases myocardial 6-keto-PGF1␣ levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice. Male C57BL/6 wild-type (WT), eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice received 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 Pio (Pioϩ) or water alone (PioϪ) 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 Ϯ 1.4% vs. 39.0 Ϯ 1.1%; P Ͻ 0.001), as well as in the eNOS Ϫ/Ϫ (32.0 Ϯ 1.6% vs. 44.2 Ϯ 1.9%; P Ͻ 0.001) and iNOS Ϫ/Ϫ (18.0 Ϯ 1.2% vs. 45.5 Ϯ 2.3%; P Ͻ 0.001) mice. The protective effect of Pio in eNOS Ϫ/Ϫ mice was smaller than in the WT (P Ͻ 0.001) and iNOS Ϫ/Ϫ (P Ͻ 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS Ϫ/Ϫ mice. iNOS was undetectable in all six groups. Pio increased cPLA 2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ , mice. Pio increased the myocardial 6-keto-PGF 1␣ levels and cPLA2 and COX2 activity in the WT, eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ 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. endothelial nitric oxide synthase; inducible nitric oxide synthase; peroxisome proliferator-activated receptor-␥ PROTECTION AGAINST ischemia-reperfusion injury may have a potential benefit in three distinct clinical situations: 1) limiting reperfusion injury in patients presenting with ST-elevation acute myocardial infarction before undergoing reperfusion therapy; 2) short-to intermediate-term treatment before elective procedures that may pose a risk for myocardial ischemia, such as cardiac or noncardiac surgery or percutaneous coronary interventions; and 3) long-term treatment in patients with established coronary artery disease to minimize the damage from an effort-induced ischemia or a potential future myocardial infarction. In the present study we studied whether the myocardial protection effects of intermediate-term pretreatment with pioglitazone (Pio) is dependent on nitric oxide (NO) synthases (NOSs), using a model that may be relevant to the second option mentioned above....

Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2

“…Neilan et al (25) reported that genetic disruption of COX-2 increases cardiac dysfunction after treatment with doxorubicin due to an increase in apoptosis of cardiac cells, suggesting that COX-2 and prostacyclin modulate the expression of genes encoding for proteins involved in apoptosis. Ye et al (26) reported that the myocardial protective effect of PIO is iNOS-independent and may be only partially dependent on eNOS. Up-regulation of COX-2 by PIO is independent of NOS (26).…”

“…Ye et al (26) reported that the myocardial protective effect of PIO is iNOS-independent and may be only partially dependent on eNOS. Up-regulation of COX-2 by PIO is independent of NOS (26).…”

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Some of the newer antidiabetic agents have also been reported to limit infarct size in the diabetic and nondiabetic heart, including 1) thiazolidinediones, such as rosiglitazone (Morrison et al, 2011;Palee et al, 2013) and pioglitazone (Ye et al, 2008;; 2) GLP-1 analogs, such as liraglutide (Noyan-Ashraf et al, 2009) and exenatide (Timmers et al, 2009); and 3) dipeptidyl peptidase-4 inhibitors, such as sitagliptin (Sauve et al, 2010;Ye et al, 2010a;Hausenloy et al, 2013b) and vildagliptin . The novel antidiabetic agent mitiglinide (Ogawa et al, 2007) has been found to affect the efficacy of preconditioning or postconditioning in the diabetic heart.…”

Time to Give Up on Cardioprotection?

“…[202][203][204] Calcium antagonist pretreatment is associated with cardioprotection, 205 but calcium antagonists seem not to interfere with conditioning. 206 In antidiabetic treatment, there are the sulfonylureas that interfere with cardioprotective signaling because they inhibit ATP-dependent potassium channel activation, 187,207 whereas some glitazones, 208,209 the glucagonlike peptide 1 analog exenatide, [210][211][212] and some dipeptidyl peptidase 4 inhibitors 213,214 protect per se. Only high-dose aspirin that blocks both cyclo-oxygenase 1 and 2 seems to interfere with cardioprotection.…”