Abstract 551: Distinct Transcriptional Roles for Wildtype vs. Truncated Nrf2 in the Heart of Transgenic Mice

Abstract

Background: Nuclear erythroid-2 like factor-2 (Nrf2), a redox-sensitive transcriptional regulator of cytoprotective and antioxidant genes. Despite the basal transcription of antioxidants/redox genes, forced activation of Nrf2 may lead to “reductive stress” (RS). In this study, we hypothesized that controlled vs. sustained activation of Nrf2 differentially regulates the myocardial transcriptome, which elucidates the transition of a physiological adaptation to pathological process. Methods: Cardiac specific Nrf2 transgenic mice expressing full length Nrf2 (FL-TG) and truncated Nrf2 (TR-TG), and their non-transgenic littermates (NTG) in the C57/BL6J backround at the age of 6-8 months were used for this study. Next generation RNA sequencing was performed using the myocardial mRNA obtained from FL-TG, TR-TG and NTG mice (n=3/group). Validation of the NGS data was carried out by qPCR analysis using specific primers for the targeted genes(n=4 to 6/group). Results: Analysis of the NGS data uncovered eccentric genomic profiles in the myocardium of mice with a 310 differentially regulated genes (DEGs) in FL-TG ( vs. NTG) and 472 DEGs in TR-TG ( vs. NTG). A closer evaluation reveals 397 and 237 DEGs commonly shared between FL-TG and TR-TG, respectively. STRING analysis revealed genomic networks involve in oxidoreductase, antioxidant and glutathione transferase were differentially altered between TL-TG vs. TR-TG groups. For instance, within the glutathione synthesis pathway, Gclm transcript was upregulated 6.0 fold (FL-TG) and 8.0 fold (TR-TG) when compared to NTG. Indeed, a significant douwnregulation of stress response genes Hspa1b (5.0 & 2.0 fold) and Hsph1 (2.0 & 2.2 fold) was apparent in between the groups. An eccentric cytoskeletal disarrangement ( Efnb3, Map1a, Acta ), an impaired protein quality control ( Bin1,Myl4 ) and a reduced cardiac function ( Timp4) were significantly downregulated in both the groups. Conclusion: These findings conclude that transgenic expression of wild-type vs. mutant forms of Nrf2 in the heart uniquely regulate the myocardial transcriptome, which might result in independent pathological processes.