Abstract P263: Mechanism for Reductive Stress in Mutant Protein Aggregation Cardiomyopathy
Background: We recently demonstrated that the hR120GCryAB associated with protein aggregation cardiomyopathy (PAC) causes reductive stress (RS) linked to dysregulation of G6PD in mice (Rajasekaran et.al Cell, 2007). Nrf2 (nuclear erythroid related factor -2) is the master transcription factor that regulates induction of genes encoding antioxidant responsive element (ARE) dependent pathways. However, the temporal effects of reductive stress on the molecular mechanisms of transcriptional regulation of Nrf2 - Keap1 pathway are unknown.
Methods: Age-matched control and mutant TG mice at 3 and 6 months with RS were used to assess activation and nuclear translocation of Nrf2 and ARE-dependent transcriptional mechanisms. Electron paramagnetic resonance (EPR) analysis was used to measure the ROS and RNS in heart tissues.
Results: Nuclear translocation of Nrf2 was significantly increased in compensated hR120GCryAB transgenic mice at 3 months compared with controls. EPR analysis revealed significantly increased ROS (superoxide, hydrogen peroxide and nitroxide) in 3-month old hR120GCryAB TG compared with controls. In contrast, hR120GCryAB-TG mice at 6-months exhibiting cardiac hypertrophy and RS (i.e., increased GSH/GSSG ratio) had attenuated ROS/RNS levels that were indistinguishable from age-matched controls.
Conclusions: Oxidative stress triggers the activation of redox sensitive Nrf2-Keap1 pathway, which might be targeted therapeutically to prevent pathogenic transition and reductive stress-induced hR120GCryAB cardiomyopathy and heart failure.
- © 2011 by American Heart Association, Inc.