Abstract 15960: Activation of TRAF2-NF-κB Signaling suppresses Mitochondrial Perturbations in Doxorubicin Cardiotoxicity
Doxorubicin (dox) is a highly effective anti-tumour agent, however, its use is limited by its protracted and cardiotoxic effects that manifest as heart failure. The canonical NFκB signaling pathway has been suggested to play a critical survival role in cardiac myocytes. Herein, we demonstrate that, impaired TRAF2 signaling disrupts NFκB activation in hearts of mice treated with dox (20mg/kg) or ventricular myocytes treated with dox (10μM). This was accompanied by severe ultrastructural defects including vacuolization, mitochondrial perturbations including mPTP, loss of [[Unable to Display Character: ∆]]Ψm and ROS production. Further we investigated role of TRAF2 on IKKβ- NFκB signaling in ventricular myocytes. Interestingly, TRAF2 mediated K-63 poly-ubiquitination of Receptor Interacting Protein 1 (RIP1) which recruits Tak-1 complex and activates IKKβ -NF-κB signaling was impaired in cells treated with dox. This coincided with a marked increase in expression and mitochondrial targeting of the Bcl-2 death protein Bnip3. Interestingly, expression of wild type TRAF2 but not the ring finger domain mutant defective for ubiquitination, restored TAK1-IKKβ-NF-κB signaling and suppressed Bnip3 gene activation in cells treated with dox. Concordant with TRAF2’s ability to suppress Bnip3, was accompanied by reduction in dox induced mPTP, ROS and cell death. Hence, our findings reveal a novel signaling pathway that functionally couples TRAF2 mediated NF-κB signaling to mitochondrial function and survival of cardiac myocytes.
Author Disclosures: R. Dhingra: None. L.A. Kirshenbaum: None.
- © 2014 by American Heart Association, Inc.