Reduction in Cardiac STAT3 Phosphorylation at Site Ser-727 Subsequent to mTOR Overactivation Exacerbated Myocardial Ischemia Reperfusion Injury in Type 1 Diabetic Rats

Reduced levels of myocardial STAT3 activity in diabetic hearts may contribute to the increased susceptibility to ischemia-reperfusion injury (I/RI). The protein mammalian target of rapamycin (mTOR) can regulate metabolism and cell processes and plays major roles in the dynamics of I/RI. However, the role of mTOR in the regulation of myocardial STAT3 and thereby its impact on myocardial I/RI in diabetes at relatively late stages of the disease is unknown. Type Ι diabetes was induced by Streptozotocin in Sprague-Dawley rats. Myocardial I/RI was achieved with coronary occlusion for 30 minutes followed by reperfusion for 2 hours in the absence or presence of the mTOR inhibitor rapamycin. In vitro cardiomyocyte hypoxia/re-oxygenation (H/R) was established in H9C2 cells. In type Ι diabetic rats, myocardial levels of troponin-I (Tn- I), lipid peroxidation products 15-F2t-Isoprostane (15-F2t-Iso) and malondialdehyde (MDA), and the protein expression of mTOR were all significantly increased?while SOD activity and the level of phosphorylated STAT3 (p-STAT3-Ser727) were both significantly decreased compared to non-diabetic rats. Myocardial I/RI significantly increased the infarct size and further increased the mTOR activation and decreased p- STAT3-Ser727 compared to diabetic rats without I/RI. The selective mTOR inhibitor rapamycin reversed these changes and conferred cardioprotective effect. In H9C2 cells, high glucose (HG) significantly increased lactic dehydrogenase (LDH) release, apoptosis cells, reactive oxygen species (ROS) production and the activation of mTOR, but decreased p-STAT3-Ser727. H/R further increased cellular injury, while mTOR gene knock-down significantly reduced H/R injury. It is concluded that myocardial mTOR was enhanced in type I diabetes which is attributable to the increased myocardial susceptibility to I/RI. Enhancing cardiac p-STAT3-Ser727 may represent a mechanism by which mTOR inhibition attenuated myocardial I/RI in type I diabetes.