Tandem Mass Tagging Based Identification of Proteome Signatures for Reductive Stress Cardiomyopathy

• Type of Material: Article
• Authors: Sini Sunny, University of Alabama Birmingham; Arun Jyothidasan, University of Alabama Birmingham; Cynthia L David, University of Arizona; Krishna Parsawar, University of Arizona; Arul Veerappan, New York University; Dean Jones, Emory University; Steven Pogwizd, University of Alabama Birmingham; Namakkal S Rajasekaran, University of Alabama Birmingham
• Language: English
• Date: 2022-06-13
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Sunny, Jyothidasan, David, Parsawar, Veerappan, Jones, Pogwizd and Rajasekaran.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fcvm.2022.848045
• Title of Journal or Parent Work: FRONTIERS IN CARDIOVASCULAR MEDICINE
• Volume: 9
• Start Page: 848045
• End Page: 848045
• Grant/Funding Information: This study was peripherally supported by funding from NHLBI (2HL118067 and HL118067) and NIA (AG042860) and the start-up funds (for NR) by the Department of Pathology and School of Medicine, the University of Alabama at Birmingham, AL, and UAB-AMC21 grant by the University of Alabama at Birmingham, AL and the Stony Wold-Herbert Fund (for AV).
• Keywords: Cardiovascular System & Cardiology; Science & Technology; myocardial proteome; reductive stress; Tandem Mass Tag proteomic analysis; Cardiac & Cardiovascular Systems; REACTIVE NITROGEN; Life Sciences & Biomedicine; speckle tracking echocardiography; caNrf2
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2), a redox sensor, is vital for cellular redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2-TG) exhibit reductive stress (RS). In this study, we identified novel protein signature for RS-induced cardiomyopathy using Tandem Mass Tag (TMT) proteomic analysis in heart tissues of TG (CaNrf2-TG) mice at 6–7 months of age. A total of 1,105 proteins were extracted from 22,544 spectra. About 560 proteins were differentially expressed in TG vs. NTg hearts, indicating a global impact of RS on the myocardial proteome. Over 32 proteins were significantly altered in response to RS -20 were upregulated and 12 were downregulated in the hearts of TG vs. NTg mice, suggesting that these proteins could be putative signatures of RS. Scaffold analysis revealed a clear distinction between TG vs. NTg hearts. The majority of the differentially expressed proteins (DEPs) that were significantly altered in RS mice were found to be involved in stress related pathways such as antioxidants, NADPH, protein quality control, etc. Interestingly, proteins that were involved in mitochondrial respiration, lipophagy and cardiac rhythm were dramatically decreased in TG hearts. Of note, we identified the glutathione family of proteins as the significantly changed subset of the proteome in TG heart. Surprisingly, our comparative analysis of NGS based transcriptome and TMT-proteome indicated that ~50% of the altered proteins in TG myocardium was found to be negatively correlated with their transcript levels. In association with the altered proteome the TG mice displayed pathological cardiac remodeling.