Journal
CIRCULATION-HEART FAILURE
Volume 6, Issue 2, Pages 335-343Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.112.000061
Keywords
Bnip3; cell death; hypoxia; mTOR; NF-kappa B
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- Heart and Stroke Foundation of Canada
- Manitoba Health Research Council
- IMPACT-Manitoba Health Research Council
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Background-Tumor necrosis factor-alpha and other proinflammatory cytokines activate the canonical Nuclear Factor (NF)-kappa B pathway through the kinase IKK beta. Previously, we established that IKK beta is also critical for Akt-mediated NF-kappa B activation in ventricular myocytes. Akt activates the kinase mammalian target of rapamycin ( mTOR), which mediates important processes such as cardiac hypertrophy. However, whether mTOR regulates cardiac myocyte cell survival is unknown. Methods and Results-Herein, we demonstrate bidirectional regulation between NF-kappa B signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKK beta resulted in mTOR activation and conversely overexpression of mTOR lead to NF-kappa B activation. Loss of function approaches demonstrated that endogenous levels of IKK beta and mTOR also signal through this pathway. NF-kappa B activation by mTOR was mediated by phosphorylation of the NF-kappa B p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-kappa B activation by the canonical tumor necrosis factor-alpha pathway. Our previous work has shown that NF-kappa B signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-kappa B activation resulting in increased Bnip3 expression and cell death. Conversely, mTOR overexpression suppressed Bnip3 levels and cell death of ventricular myocytes in response to hypoxia. Conclusions-To our knowledge, these data provide the first evidence for a bidirectional link between NF-kappa B signaling and mTOR that is critical in the regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of this axis may be cardioprotective during ischemia.
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