title: Sex-specific mTOR signaling determines sexual dimorphism in myocardial adaptation in normotensive DOCA-salt model.
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 wild-type mice. Radio-telemetric 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 rapamycin-treated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCA-salt 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. Vehicle-treated wild-type females maintained their high constitutive mTORC1 and mTORC2 in response to DOCA-salt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ERβ(-/-) DOCA-salt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ERβ-dependent regulation involves sex-specific 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 sex-specific therapeutic strategies in left ventricular hypertrophy.
authors: Department of Nephrology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Dennis
authors: D
authors: Gürgen
authors: Angelika
authors: A
authors: Kusch
authors: Robin
authors: R
authors: Klewitz
authors: Uwe
authors: U
authors: Hoff
authors: Rusan
authors: R
authors: Catar
authors: Björn
authors: B
authors: Hegner
authors: Ulrich
authors: U
authors: Kintscher
authors: Friedrich C
authors: FC
authors: Luft
authors: Duska
authors: D
authors: Dragun
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D003900:Desoxycorticosterone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000502:physiology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008901:Mineralocorticoids / Q000008:administration & dosage*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020123:Sirolimus / Q000627:therapeutic use; D013318:Stroke Volume / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D047629:Estrogen Receptor beta; D008901:Mineralocorticoids; D003900:Desoxycorticosterone; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus