Abstract-The deoxycorticosterone acetate (DOCA)salt mouse model exhibits adverse cardiac remodeling in male mice and cardiac protection in female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling is necessary for cardiac protection in females. We first tested sex differences and intracellular signaling after mTOR targeting with rapamycin in wildtype mice. Radiotelemetric blood pressure was maintained at normal for 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection fraction, inhibited fibrosis, and maintained capillary structure in male mice. Decreased mTORC1 and increased mTORC2 activity were detected in rapamycintreated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCAsalt females lacking the estrogen receptor β (ERβ −/− ) that we described earlier. Because rapamycin downregulated ERβ in female mice, we next studied ERβ −/− normotensive DOCA salt females. Vehicletreated wildtype females maintained their high constitutive mTORC1 and mTORC2 in response to DOCAsalt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ERβ −/− DOCAsalt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ERβdependent regulation involves sexspecific use of mTOR signaling branches. Maintenance of both mTORC1 and mTORC2 signaling seems to be essential for adaptive cardiac remodeling in females and supports a rationale for sexspecific therapeutic strategies in left
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 (pp70S6K Thr389 ) and mTORC2 (pAkt Ser473 ) 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 pAkt Ser473 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.
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