Abstract 8: Female Sex-related Cardioprotection Relies on Estrogen Receptor-beta, mTORC1, and mTORC2 Activities
Normotensive deoxycorticosterone acetate-salt (DOCA) mice retain sexual dimorphism with adverse cardiac remodeling in males and maintenance of protective phenotype in females. Genomic deletion of ERβ in DOCA mice removed this protection. We hypothesized that sex differences in mTOR signaling branches are instrumental for ERβ-mediated cardioprotection in females. Female and male mice with ERα and ERβ gene deletions were uninephrectomized and treated with DOCA for 6 weeks. Hydralazine was used for blood-pressure normalization under telemetric control. Echocardiography was used to determine left ventricular dimensions and function. In additional studies, we used rapamycin to inhibit mTOR in wild-type (WT) mice. While ERα deletion had no significant impact on cardiac phenotype and function, ERβ-/- female DOCA mice showed the maladaptive cardiac phenotype as recently reported. Signal transduction analysis revealed high mTORC1 (pp70S6KThr389) and mTORC2 (pAktSer473) activation in WT DOCA females, but not in WT DOCA males, which was also lost in DOCA ERβ-/- females. Rapamycin-treated male DOCA mice showed functional benefit from intervention and reduced left ventricular hypertrophy (LVH). Heart weight to tibia length (HW/TL; mg/mm) was as follows: control/DOCA 7.1±0.2 / 8.7±0.2, rapamycin control/DOCA 7.0±0.2 / 7.9±0.2) with preserved ejection fraction. This state-of-affairs was associated with increased mTORC2 activity as measured by pAktSer473 upregulation (DOCA 0.8±0.2, rapamycin DOCA 2.2±0.3). In contrast, females displayed a further 14% LVH increase with rapamycin (HW/TL control/DOCA 6.4±0.1 / 7.4±0.1, rapamycin control/DOCA 6.1±0.2 / 7.9±0.2) and developed a dilative cardiac phenotype similar to ERβ-/- females (LVIDd [mm] DOCA/rapamycin DOCA 4.18±0.06 / 4.31±0.08, IVSd [mm] DOCA/rapa DOCA 0.6±0.02 / 0.5±0.02). Remarkably, in contrast to males, rapamycin intervention decreased not only mTORC1, but also mTORC2 activity in females (DOCA 1.7±0.2, rapamycin DOCA 0.9±0.1). Our findings implicate ERβ-dependent sex-specific regulation of mTOR signaling. Maintenance of mTORC1 and mTORC2 signaling appears to be essential for adaptive cardiac remodeling what provides a rationale for sex-specific therapeutic strategies in LVH.
- © 2012 by American Heart Association, Inc.