Abstract P152: Cardiac mTOR Preserves Cardiac Function and Inhibits the Inflammatory Response After Transient Ischemia
Recent reports strongly suggested that the mammalian target of rapamycin (mTOR) is necessary for cardiomyocyte survival in pathological cardiac hypertrophy. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg), we reported that cardiac mTOR is sufficient to protect the heart against heart failure in pathological hypertrophy, accompanied by a decrease in production of proinflammatory cytokines. However, the role of cardiac mTOR in ischemic cardiac injury remains undefined. To assess the effects of cardiac mTOR in cardiac ischemia, we studied the response of hearts from mTOR-Tg mice to global ischemia-reperfusion injury (IRI) (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. mTOR-Tg mice demonstrated improved functional recovery compared with littermate control (WT) mice [percent recovery of LV developed pressure (LVDP); 44.6±7.3 vs. 24.7±5.3 %, mTOR-Tg vs. WT, n=9 each, p<0.05]. Biochemical analyses demonstrated that the level of mTOR protein decreased under IRI stress in WT while the level of mTOR protein in post-IRI mTOR-Tg mice was comparable to non-ischemic control mice. Both mTORC1 (p70S6K) and mTORC2 (Akt) activation in mTOR-Tg mice were increased by IRI, while these were not changed in WT mice after IRI. Quantitative RT-PCR demonstrated that expression of proinflammatory cytokines in mTOR-Tg mice after IRI was significantly lower than WT mice (IL-6, 7.1±1.5 vs. 14.6±1.6, p<0.005; TNF-alpha, 2.1±0.4 vs. 5.1±0.8, p<0.01; post-IRI mTOR-Tg mice vs. WT mice, fold change over non-ischemic control WT mice, n=9 each). To further characterize the inflammatory response, we measured cytokine in the effluent samples by ELISA. We observed that secretion of IL-6 in post-IRI mTOR-Tg mice was significantly lower than that in WT mice (50.1±11.5 vs. 95.6±23.8 pg/ml, post-IRI mTOR mice vs. post-IRI WT mice, n=9 each, p<0.05). IL-6 is known as a strong prognostic predictor in patients with heart failure. Taken together, these findings suggest that cardiac mTOR is sufficient to substantially preserve cardiac function and prevent the inflammatory response, which may have relevance for settings in heart failure.
- © 2011 by American Heart Association, Inc.