Abstract 11402: Cardioprotective Effects Of mTOR Against Ex Vivo Ischemia-reperfusion Injury In Diet-induced Obese Mice
The risk of heart failure following myocardial infarction is higher in diabetic patients than nondiabetic patients. The mechanistic target of rapamycin (mTOR) is a key molecule of the insulin signaling in regulation of cell growth and survival. Our recent report using transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) showed that cardiac mTOR protects the heart against ischemia/reperfusion (I/R) injury. However, the effect of mTOR on cardioprotection in metabolic syndrome has not been well defined. To address this question, we studied the effect of overexpression of cardiac mTOR on cardiac function following I/R in mice with high-fat diet (HFD)-induced obesity using mTOR-Tg mice. mTOR-Tg and WT mice were fed HFD (60% fat by calories) for 14 weeks. Body weight and heart weight were higher in HFD group than normal chow diet (NCD) group (p<0.001 in both strains), but there was no difference between HFD-mTOR-Tg and HFD-WT mice. Glucose intolerance and insulin resistance induced by HFD determined by glucose and insulin tolerance tests were comparable between HFD-WT and HFD-mTOR-Tg mice. Hearts from four groups were subjected to global I/R (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. The functional recovery after I/R was significantly higher in mTOR-Tg than WT hearts in NCD group as previously reported [percent recovery of left ventricular developed pressure (LVDP), 44.0 ± 4.7 vs. 60.5 ± 4.2 %, NCD-WT (n=14) vs. NCD-mTOR-Tg (n=16), p<0.05]. HFD treatment significantly reduced LVDP recovery in HFD-WT hearts than NCD-WT hearts [44.0 ± 4.7 vs. 14.0 ± 4.7 %, NCD-WT vs. HFD-WT (n=13), p<0.01]. Intriguingly, HFD-mTOR-Tg indicated significantly higher LVDP recovery compared to HFD-WT hearts [14.0 ± 4.7 vs. 33.3 ± 6.6 %, HFD-WT vs. HFD-mTOR-Tg (n=15), p<0.05]. To evaluate cardiomyocyte injury, we measured creatine kinase (CK) and lactate dehydrogenase (LDH) concentration in the effluent following I/R. The amount of CK and LDH secreted from HFD-mTOR-Tg hearts was less than that from HFD-WT hearts. These findings suggest that cardiac mTOR is sufficient to substantially limit the metabolic syndrome-induced cardiac dysfunction following I/R in a mouse model of obesity with glucose intolerance and insulin resistance.
- © 2012 by American Heart Association, Inc.