Abstract
Background: Nuclear factor erythroid 2-related factor 2 (NRF2) signaling is vital for redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2) exhibit reductive stress (RS). Here in, we identified novel protein signatures reacting to RS-induced cardiomyopathy. Methods: Tandem Mass Tag (TMT) proteomic analysis was performed in the heart tissues of Ca-Nrf2-transgenic (TG-low & TG-high) and non-transgenic (NTg) mice at 6 months of age (N= 4/group). Differentially expressed proteins (DEPs) were then identified using Scaffold. Validated the key DEPs using immunoblotting. PANTHER and STRING analysis were used to identify potential targets and their interactions. Results: A total of 1105 proteins were extracted from 24369 spectra. Of note, 226 and 261 proteins were differentially expressed in TG-L and TG-H vs. NTg hearts indicating a unique proteome signature for RS. Heat map analysis revealed a clear distinction between the TG-L and TG-H due to the dose-dependent effects of transgene/RS. Majority of the DEPs that are significantly altered in RS mice found to involve in stress related pathways such as antioxidants, NADPH, protein quality control (PQC), etc. Interestingly, some of these proteins were redox modified at their cysteine residues under chronic RS setting. Conclusions: TMT based proteomic analyses revealed unique proteome signatures for RS. The cysteine modifications in multiple proteins likely to cause pathological alterations via impaired PQC mechanisms. Molecular studies related to RS-mediated redox modifications in structural and functional cardiac proteome are underway.
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