P101The effect of rapamycin in cardiac mTORC2-deficient mice under pressure overload conditions

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Abstract

Aims: Mammalian target of rapamycin (mTOR) is a central regulator of cellular growth and metabolism and has distinct substrates with tissue-specific functions depending on whether it is part of the multiprotein complex mTORC1 or mTORC2. Rapamycin has been reported to attenuate the development of cardiac hypertrophy and regress established hypertrophy in aortic-banded mice without reducing cardiac function. Short-term rapamycin treatment increases Akt phosphorylation via mTORC2, which may promote cell survival. The molecular effects and involvement of mTORC2 in long-term rapamycin treatment are not known in the heart.

Methods: Rictor, an essential and specific component of mTORC2, was deleted in 10 weeks-old male mice homozygous for floxed rictor and expressing cre-recombinase (MerCreMer) under control of the α-MHC-promoter (rictor-cKO mice). Three weeks after tamoxifen, the aorta was ligated (TAC). Rapamycin (2 mg×kg-1×d-1) or vehicle was administered daily from the day before until 7 days after surgery. Echocardiography was performed before and 7 days after surgery. Mice were sacrificed after the last echo and the hearts harvested for histology, protein and RNA analysis.

Results: TAC led to significant increases in left ventricular mass and decreases in cardiac function. Post-mortem analysis revealed that all rapamycin-treated mice had lower ventricular weight/body weight ratios than the corresponding vehicle-treated groups. However, only rapamycin-treated control mice showed improved cardiac function after TAC (EF: 48.6±2.0% for rapamycin and 30.8±3.1% for vehicle, p<0.001). The effect of rapamycin in rictor-cKO mice was less pronounced (EF: 37.0±3.6% for rapamycin and 25.8±3.7% for vehicle, p=0.06). The inhibition of mTORC1 by rapamycin was confirmed as phosphorylation of p70-S6K was suppressed. Rictor deficiency reduced the phosphorylation of the mTORC2 target Akt at S473, and rapamycin treatment further decreased its phosphorylation. In the control group, phosphorylation of Akt at S473 was also blocked by rapamycin.

Conclusions: Rapamycin attenuated pressure overload-induced hypertrophy in both control and rictor-deficient mice, but cardiac function was significantly improved only in the control group. Prolonged rapamycin treatment not only inhibited mTORC1 activities but also blocked mTORC2-mediated Akt phosphorylation. Despite blockade of several mTOR targets by rapamycin, some rapamycin-insensitive activities of mTOR appear to be cardioprotective.

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