Abstract 232: The Mammalian Target of Rapamycin Plays a Critical Role in the Development of Cardiac Hypertrophy in Spontaneously Hypertensive Rats
Recent studies using exercise trained and genetically engineered rodents have identified the mammalian target of rapamycin (mTOR) as a critical regulator of physiological cardiac hypertrophy. However, the contribution of mTOR to cardiac hypertrophy in the Spontaneously Hypertensive Rat (SHR), a strain that slowly develops hypertension after ~6 weeks of age and pathological hypertrophy during adulthood, is unknown. We hypothesized that mTOR regulates the initial development of hypertrophy in the SHR. Blood pressure, cardiac hypertrophy, and activation of the mTOR pathway were determined in young (10 week-old) and adult (16 week-old) SHR and normotensive Wistar Kyoto (WKY) rats (n=6 per group). Systolic blood pressure (mmHg) was increased (p<0.001) in young SHR (162±3) vs. WKY (128±1) rats, and even further elevated (p<0.001) in adult SHR (184±7) vs. WKY (138±2). Only adult SHR had cardiac hypertrophy evidenced by a ~22% increase in heart:body weight (p<0.001). Young SHR had increased (p<0.01) activation of Akt and P70S6K (components of the mTOR signaling pathway). To determine whether mTOR regulates cardiac growth in SHR rats during this developmental phase of hypertrophy, 13 week-old rats were treated with 2 mg/kg/day rapamycin i.p. (n=9 SHR-Rap) or vehicle (saline, n=6 SHR-Veh, n=7 WKY-Veh) for 3 weeks. Rapamycin inhibition of cardiac mTOR was evident by a ~4-fold reduction (p<0.001) in phosphorylation of the mTOR substrates S6 ribosomal protein and eukaryotic translation initiation factor-4E binding protein-1 in SHR-Rap vs. SHR-Veh and WKY-Veh. In spite of greater (p<0.001) systolic blood pressure in SHR-Rap (213±8) vs. SHR-Veh (189±6), SHR-Rap displayed a 47±6% reduction (p<0.001) in heart weight, and a 53±7% reduction (p<0.001) in developed hypertrophy (heart:tibia length). These data indicate that mTOR is required for full development of cardiac hypertrophy evoked by rising blood pressure in the SHR. Given that these data are obtained from a clinically relevant model of evolving blood pressure, we conclude that mTOR plays a role in development of pathological hypertrophy, and that these data may be clinically relevant to humans who experience cardiac hypertrophy due to hypertension.