Bidirectional regulation of nuclear factor- B and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes

Dhingra, R, Gang, H, Wang, Y, Biala, A, Aviv, Y, Margulets, V, Tee, Andrew ORCID: https://orcid.org/0000-0002-5577-4631 and Kirshenbaum, L 2013. Bidirectional regulation of nuclear factor- B and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes. Circulation: Heart Failure 6 (2) , pp. 335-343. 10.1161/CIRCHEARTFAILURE.112.000061

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Abstract

BACKGROUND: Tumor necrosis factor-α and other proinflammatory cytokines activate the canonical nuclear factor (NF)-κB pathway through the kinase IKKβ. Previously, we established that IKKβ is also critical for Akt-mediated NF-κB 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-κB signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKKβ resulted in mTOR activation and conversely overexpression of mTOR lead to NF-κB activation. Loss of function approaches demonstrated that endogenous levels of IKKβ and mTOR also signal through this pathway. NF-κB activation by mTOR was mediated by phosphorylation of the NF-κB p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-κB activation by the canonical tumor necrosis factor-α pathway. Our previous work has shown that NF-κB signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-κB 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-κB 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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Animals;Animals, Newborn;Cell Hypoxia;Cell Survival;Cells, Cultured;Enzyme Activation;Gene Expression Regulation;I-kappa B Kinase/genetics;I-kappa B Kinase/metabolism;Membrane Proteins/genetics;MembraneProteins/metabolism*;Mitochondrial Proteins;Myocytes, Cardiac/drug effects;Myocytes, Cardiac/enzymology*;Myocytes, Cardiac/pathology;NF-kappa B/genetics;NF-kappa B/metabolism*;Phosphorylation;Promoter Regions, Genetic;Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins/genetics;Proto-Oncogene Proteins/metabolism*;Proto-Oncogene Proteins c-akt/metabolism;RNA Interference;Rats;Rats, Sprague-Dawley; Signal Transduction*/drug effects;Sirolimus/pharmacology;TOR Serine-Threonine Kinases/antagonists & inhibitors;TOR Serine-Threonine Kinases/genetics;TOR Serine-Threonine Kinases/metabolism*;Transcription Factor RelA/metabolism; Transcription, Genetic;Transfection;Tumor Necrosis Factor-alpha/metabolism; I-kappa B Kinase/metabolism Membrane Proteins/genetics Membrane Proteins/metabolism* Mitochondrial Proteins Myocytes, Cardiac/drug effects Myocytes, Cardiac/enzymology* Myocytes, Cardiac/pathology NF-kappa B/genetics NF-kappa B/metabolism* Phosphorylation Promoter Regions, Genetic Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins/genetics Proto-Oncogene Proteins/metabolism* Proto-Oncogene Proteins c-akt/metabolism RNA Interference Rats Rats, Sprague-Dawley Signal Transduction*/drug effects Sirolimus/pharmacology TOR Serine-Threonine Kinases/antagonists & inhibitors TOR Serine-Threonine Kinases/genetics TOR Serine-Threonine Kinases/metabolism* Transcription Factor RelA/metabolism Transcription, Genetic Transfection Tumor Necrosis Factor-alpha/metabolism
Publisher:	American Heart Association
ISSN:	1941-3289
Last Modified:	23 Oct 2022 13:13
URI:	https://orca.cardiff.ac.uk/id/eprint/110011

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