Abstract 19126: Novel Linkage Between Metabolic Sensor Mechanistic Target of Rapamycin (mTOR) and Canonical NF-kB Signaling Pathway Preserves Mitochondrial Integrity in Ventricular Myocytes During Hypoxia

Abstract

Background: TNFα and other pro-inflammatory cytokines activate the canonical NF-kB pathway through the IkBa kinase (IKK) signaling complex. IKKβ kinase is also critical for Akt-mediated NF-κB activation in ventricular myocytes. Akt activates the kinase (mechanistic target of rapamycin (mTOR), which mediates important processes such as metabolism protein synthesis and autophagy. However, mTOR’s role in regulating cardiac myocyte cell survival is unknown. Methods and Results: Herein, we demonstrate bi-directional regulation between NF-kB signaling and mTOR, the balance of which determines ventricular myoctye 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-kB activation by mTOR was medated by phosphorylation of the NF-kB p65 subunit at S276 increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-κB activation by the canonical TNFα pathway. Inhibition of mTOR with rapamycin or during hypoxia decreased NF-kB activation resulting in increased mitochondrial PTP opening, maladaptive autophagy and necrotic cell death. Conversely, mTOR over-expression suppressed mitochondrial injury, autophagy and cell death of ventricular myocytes during hypoxia as well as nutrient deprivation. Conclusions: To our knowledge, these data provide the first evidence for a bi-directional link between NF-kB signaling and mTOR that is critical in the regulation of cardiac myocyte death. Hence, modulation of this axis may be cardioprotective in attenuating metabolic stress induced during hypoxia.