Pivotal role of mTORC2 and involvement of ribosomal protein S6 in cardioprotective signaling

Toshiyuki Yano, Marcella Ferlito, Angel Aponte, Atsushi Kuno, Tetsuji Miura, Elizabeth Murphy, Charles Steenbergen

Research output: Contribution to journalArticle

Abstract

Rationale: There is tight coupling between Akt activation and suppression of cell death. Full Akt activation requires mammalian target of rapamycin complex 2 (mTORC2), but the regulation of mTORC2 is unclear. Objective: To gain new insights into mechanisms of mTORC2/Akt signaling. Methods and results: The role of mTORC2 in cardioprotection was examined. In perfused mouse hearts, ischemic preconditioning increased mTORC2 activity, leading to phosphorylation of Akt on Ser473. The protective effect of ischemic preconditioning was lost by pretreatment with dual mTORC inhibitors but not with rapamycin, an mTORC1 inhibitor, which indicates the fundamental role of mTORC2 activation in cardioprotection. Next, the regulation and downstream targets of mTORC2/Akt signaling were explored. We have found that ischemic preconditioning and other Akt activators (insulin and opioids) result in phosphorylation of ribosomal protein S6 (Rps6) at Ser235/236 in mouse hearts and neonatal rat ventricular myocytes. Rps6 interacts with components of mTORC2, and siRNA-mediated knockdown of Rps6 attenuates insulin-induced mTORC2 activation and Akt-Ser473 phosphorylation. On the other hand, Rps6 overexpression enhanced Akt-Ser473 phosphorylation, indicating that Rps6 activation amplifies mTORC2/Akt signaling. Disruption of the Rps6/mTORC2 pathway by knockdown of Rps6 or rictor abrogated insulin-induced cytoprotection against oxidative stress. Although rapamycin blocks Rps6-dependent mTORC2 activation, mTORC2 is still activated by an alternative signaling pathway, demonstrating the redundancy in cardioprotective signaling. Conclusions: Activation of mTORC2 plays a pivotal role in cardioprotection, and Rps6 is a convergence point of cardioprotective signaling, providing positive feedback regulation of mTORC2/Akt signaling.

Original languageEnglish (US)
Pages (from-to)1268-1280
Number of pages13
JournalCirculation research
Volume114
Issue number8
DOIs
StatePublished - Jan 1 2014

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Keywords

  • insulin
  • ischemia-reperfusion injury
  • ischemic preconditioning
  • mTORC2
  • myocardial ischemic reperfusion injury
  • rapamycin
  • sirolimus

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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