17ß-Estradiol Regulates mTORC2 Sensitivity to Rapamycin in Adaptive Cardiac Remodeling

• DOI: 10.1371/journal.pone.0123385
• Publication Date: 2015-04-16T17:57:53Z
• Authors: Angelika Kusch; Maria Schmidt; Dennis Gürgen; Daniel Postpieszala; Rusan Catar; Björn Hegner; Merci M. Davidson; Shokoufeh Mahmood...; Duska Dragun
• Keywords: mTORC2

Adaptive cardiac remodeling is characterized by enhanced signaling of mTORC2 downstream kinase Akt. In females, 17ß-estradiol (E2), as well Akt contribute essentially to sex-related premenopausal cardioprotection. Pharmacologic mTOR targeting with rapamycin increasingly used for various clinical indications, yet burdened heterogeneity in therapy responses. The drug inhibits mTORC1 and less-so mTORC2. male rodents, decreases maladaptive hypertrophy whereas it leads detrimental dilative cardiomyopathy females. We hypothesized that inhibition could interfere 17β-estradiol (E2)-mediated sexual dimorphism adaptive cell growth tested responses murine female hearts cultured cardiomyocytes. Under physiological vivo conditions, compromised function only female, but not hearts. cardiomyocytes, impaired simultaneously IGF-1 induced activation both branches, presence E2. Use specific estrogen receptor (ER)α- ERβ-agonists indicated involvement receptors (ER) effects on Classical feedback mechanisms common tumour cells upregulation PI3K were involved. E2 effect Akt-pS473 downregulation was independent ERK shown sequential MEK-inhibition. Furthermore, regulatory complex defining component rictor phosphorylation at Ser1235, known Akt-substrate binding mTORC2, altered. Functionally, significantly reduced trophic size. addition, cardiomyocytes under treatment displayed decreased SERCA2A mRNA protein expression suggesting negative functional consequences cardiomyocyte contractility. Rictor silencing confirmed regulation E2-cultured These data highlight a novel modulatory Conceivably, abrogates the "female advantage".