Overexpression of inducible nitric oxide synthase in the diabetic heart compromises ischemic postconditioning

Citation:

Tian-Tian Wang, Mao-Mao Shi, Xiao-Long Liao, Yu-Quan Li, Hao-Xiang Yuan, Yan Li, Xiang Liu, Da-Sheng Ning, Yue-Ming Peng, Fan Yang, Zhi-Wei Mo, Yu-Mei Jiang, Ying-Qi Xu, Haobo Li, Min Wang, Zhi-Jun Ou, Zhengyuan Xia, and Jing-Song Ou. 2019. “Overexpression of inducible nitric oxide synthase in the diabetic heart compromises ischemic postconditioning.” J Mol Cell Cardiol, 129, Pp. 144-153.

Abstract:

Ischemia postconditioning (PTC) can reduce myocardial ischemia/reperfusion injury. However, the effectiveness of PTC cardioprotection is reduced or lost in diabetes and the mechanisms are largely unclear. Hyperglycemia can induce overexpression of inducible nitric oxide synthesis (iNOS) in the myocardium of diabetic subjects. However, it is unknown whether or not iNOS especially its overexpression plays an important role in the loss of cardioprotection of PTC in diabetes. C57BL6 and iNOS mice were treated with streptozotocin to induce diabetes. Part of diabetic C57BL6 mice were also treated with an iNOS specific inhibitor, 1400 W. Mice were subjected to myocardial ischemia/ reperfusion with/without PTC. The hemodynamic parameters, plasma levels of cardiac troponin T (cTnT), TNF-α, IL-6 and nitric oxide (NO) were monitored. The myocardial infarct size, superoxide anion (O) generation, nitrotyrosine production and apoptosis were measured. The expression of phosphorylated Akt, endothelial NOS (eNOS), iNOS and Erk1/2 in ischemic heart were detected by immunoblot analysis. In diabetic C57BL6 and iNOS mice, the post-ischemic hemodynamics were impaired, the cTnT, TNF-α, IL-6 level, myocardial infarct size, apoptotic index, O and nitrotyrosine generation were increased and the Akt/eNOS signal pathways were inhibited. PTC improved hemodynamic parameters, reduced cTnT level, myocardial infarct size, apoptotic index, O and nitrotyrosine generation and activated Akt/eNOS and Erk1/2 signal pathways in both non-diabetic C57BL6 and iNOS mice as well as diabetic iNOS mice, but not in diabetic C57BL6 mice. PTC also increased NO production in both non-diabetic and diabetic C57BL6 and iNOS mice, and enhanced iNOS expression in non-diabetic C57BL6 mice. 1400 W restored the cardioprotection of PTC in diabetic C57BL6 mice. Our data demonstrated that PTC reduced myocardial ischemia/reperfusion injury in non-diabetic mice but not C57BL6 diabetic mice. Deletion of iNOS restored the cardioprotection of PTC in diabetic mice. Our findings suggest that iNOS plays a key role in the reduction of cardioprotection of PTC in diabetes and may provide a therapeutic target for diabetic patients.