Abstract 20550: Rictor/mTORC2 is a Critical Mediator of Cardiac Hypertrophy and Survival in Response to Pressure Overload
Mammalian target of rapamycin (mTOR) is a protein kinase which exerts its cellular functions by assembling into the multiprotein complexes 1 (mTORC1) and 2 (mTORC2) with the specific adaptor proteins raptor and rictor, respectively. Although mTORC1 is involved in the regulation of cardiomyocyte growth and survival, the specific function of mTORC2 in the heart remains to be elucidated. To address this issue, we studied the cardiac phenotype of cardiac-specific rictor knock-out (R-cKO) mice, in which mTORC1 remains intact in the heart. At baseline, the cardiac phenotype of the R-cKO mice was not significantly different from that of wild type (WT) controls. After 4 weeks of transverse aortic constriction (TAC), however, R-cKO (N=4) mice exhibited significant left ventricular (LV) dilation (4.8±0.5 vs. 4.0±0.4 mm, p<0.05) and a severe reduction in LV systolic function (FS: 19.9±10.6 vs 39.0±9.7 %, p<0.05) compared to WT mice (N=4). LV end-diastolic pressure (17.4±4.3 vs. 7.1±3.9 mmHg, p<0.05) and lung congestion (lung/BW: 14.1±0.6 vs. 8.2±0.31 mg/g,p<0.05) were significantly greater in R-cKO than in WT mice. Interestingly, LV weight/tibial length (5.5±1.0 vs. 6.8±0.7 mg/mm, p=0.09) and LV wall thicknesses (septum: 0.9±0.2 vs. 1.3±0.2 mm, p<0.05; posterior wall: 0.8±0.1 vs 1.3±0.3 mm, p<0.05) after TAC were lower in R-cKO than in WT mice, suggesting a blunted hypertrophic response in these animals. This was also confirmed by an attenuated increase in cell size after TAC in R-cKO mice (1.6±0.3 vs. 2.7±0.2 fold, vs baseline cell size, p<0.05). R-cKO mice exhibited increased myocardial apoptosis after TAC (0.16±0.06 vs. 0.09±0.02%, p<0.05), whereas the extent of fibrosis did not differ from WT. After TAC, the phosphorylation status of Akt (serine 473), a known target of mTORC2, was significantly decreased in R-cKO mice (0.32 fold, p<0.05). The phosphorylation status of FOXO1 (threonine 24), FOXO3a (threonine 32) and GSK-3β (serine 9) after TAC was also reduced in R-cKO compared to WT mice. In conclusion, mTORC2 containing rictor positively regulates cardiomyocyte growth, survival and Akt signaling and protects against cardiac dysfunction in response to pressure overload.
- © 2010 by American Heart Association, Inc.