Abstract P2045: Transcriptome Versus Proteomic Discrepancy Is Associated With Structural-functional Dys-synchrony In Reductive Stress Myocardium

Abstract

Background: A real-time action of Nrf2 in response to a stress is vital to preserve the redox homeostasis, but its activation under unstressed settings tilt the redox balance towards the reductive arm, leading to reductive stress (RS). In this study, we identified that >50% mismatch between mRNA and protein levels in RS myocardium undergoing structural/functional dys-synchrony. Methods: NGS-RNA Seq (for RNA), Tandem Mass Tagging (TMT) Mass spectrometry (for proteins) and speckle tracking strain echocardiography (STE) using Vevo2100 system was performed in the cardiac-specific constitutively active Nrf2 transgenic (CaNrf2-TG/TG) and non-transgenic (NTG) mice (n=4/group) at ~6-7 months of age. Results: Comparison of NGS and TMT data in TG vs. NTG hearts showed surprising results. Out of 104 commonly found gene products in NGS and proteins at a FC≥1.5, the levels of 50 proteins are not consistent with their RNA expression. The proteins that are steadily expressed according to their respective mRNA levels are classified as “transcription-sync proteins (T-SP)” and the ones that do not match are termed as “transcription-nonsync proteins. While changes in Nrf2-driven antioxidant genes ( Nqo1, Gsr, Gsta1-4, and Gstm1 ) were grouped under “T-SP”, other transcripts including Atp5pb, Ces1d, Cmbl, Cox7a1, Cpt1b, Fah and Gstk1 did not quantitatively match with their translated products in TG hearts. Further, STE demonstrated an impaired wall motion (diastolic and systolic velocity), increased fractional shortening (20% vs 50%; p<0.0001), decreased global longitudinal strain (-10% vs -25%, p<0.0002), increased IVRT (6.46 vs 13.8 ms; p<0.0001) and IVCT (8.06 vs 12.5 ms; p<0.0005) in TG vs. NTG mice. Changes in the systolic and diastolic functions with structural abnormalities demonstrate cardiac dys-synchronicity in TG hearts with chronic RS exhibiting impaired transcriptome and proteome profiles. Conclusions: Our comparative analysis of RNA and protein in RS hearts demonstrated that 50% of the proteins do not match with the quantitative changes of their transcripts. We highlight that the RS could be a novel mechanism for disproportionate transcription vs translation, which leads to structural and functional dys-synchrony in the TG hearts.