Abstract 1829: Transgenic mTOR Expression Protects the Heart from Pressure Overload-Induced Cardiac Dysfunction
Prior studies using rapamycin to inhibit mTOR have suggested it plays a role in maladaptive cardiac hypertrophy. However, the existence of a rapamycin-insensitive mTOR complex (mTORC2) suggests that such studies may not fully reflect the mTOR’s role in the heart. To explore this further, we generated transgenic mice with cardiac-specific overexpression of wild-type mTOR driven by the αMHC promoter. Three lines were produced and one (Tg4) was characterized in more detail. Tg4 mice exhibited normal baseline heart size despite a ~3-fold increase in cardiac-specific mTOR expression vs littermate controls (NTg), (p<0.05). Phosphorylation of S6 (Ser235/236) and Akt (Ser473) was substantially increased (32.52±0.54-fold and 2.99±0.54-fold vs NTg, respectively, p<0.05, n=3 each), suggesting enhanced signaling via both mTORC1 and mTORC2. We then used transverse aortic constriction (TAC) to study mTOR in pathological hypertrophy and cardiac dysfunction. In wild-type mice, total mTOR expression increased ~1.5-fold (p<0.05) during TAC-induced cardiac dysfunction. To understand the functional importance of TOR induction, 13-week old male Tg and NTg littermates were subjected to TAC and followed by echocardiography. By 4 weeks post-TAC, NTg had more cardiac hypertrophy than Tg4 (heart weight/tibial length (TL) ratio; 11.12±0.52 vs 8.21±0.46, p<0.01, n=6 each). NTg also had worse cardiac function than Tg4 mice (%FS; 17.09±2.36% vs 44.12±4.80%, NTg4 vs Tg4, p<0.01, n=6 each) and more evidence of heart failure with increased wet lung weight (Lung W/TL ratio; 14.42±2.73 vs, 7.67±0.90, NTg vs Tg, p<0.05, n=6 each) 4 weeks after TAC. Due to increased mTOR expression in NTg mice, the difference in total expression of mTOR between Tg and NTg at 4 weeks post-TAC was less than that seen at the baseline (1.4-fold from ~3-fold). The differences seen in p-S6 and p-Akt at baseline were no longer significant after TAC (0.80±0.19 fold and 1.02±0.13 fold increases, respectively, n=6 each). Together, these data surprisingly suggest that the increase in endogenous mTOR expression seen in pathological cardiac hypertrophy may be adaptive since enhancing mTOR further mitigates pathological hypertrophy and prevents cardiac dysfunction.