Identification of Potential Crucial Genes in Atrial Fibrillation: A Bioinformatic Analysis

Zhang, Junguo; Huang, Xin; Wang, Xiaojie; Gao, Yanhui; Liu, Li; Li, Ziyi; Chen, Xuejiao; Zeng, Jie; Ye, Zebing; Li, Guowei

doi:10.21203/rs.3.rs-15436/v4

Cited by 2 publications

(2 citation statements)

References 24 publications

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“…To gain evidence for reductome-signature in TG hearts, gene ontology pathway analysis was carried out by panther and string analysis (26,27). Panther analysis classify the proteins on the basis of biological function and pathways (28).…”

Section: Discussionmentioning

confidence: 99%

Proteome signatures of reductive stress cardiomyopathy

Sunny

Parsawar

Jones

et al. 2021

Preprint

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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 biomarkers for RS-induced cardiomyopathy using Tandem Mass Tag (TMT) proteomic analysis in heart tissues of TG (CaNrf2-TG) and non-transgenic (NTg) mice at 6-7 months of age (N= 4/group). A total of 1105 proteins were extracted from 22544 spectra. Of note, about 560 proteins were differentially expressed in TG vs. NTg hearts, indicating a global impact of RS on myocardial proteome. From a closer analysis of the proteome datasets, we identified over 32 proteins that were significantly altered in response to RS. Among these, 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. Of note, we observed several proteins with redox (#185; cysteine residues), NEM-adducts (#81), methionine-loss (#21) and acetylation (#1) modifications in TG vs. NTg hearts due to chronic RS. The majority of the differentially expressed proteins (DEPs) that are significantly altered in RS mice were found to be involved in stress related pathways such as antioxidants, NADPH, protein quality control (PQC), 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 ~50% of the altered proteins in TG myocardium was found to be negatively correlated with their transcript levels. Modifications at cysteine/NEM-adducts (redox), methionine or lysine residues in multiple proteins in response to chronic RS might be associated with impaired PQC mechanisms, thus causing pathological cardiac remodeling.

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Section: Discussionmentioning

confidence: 99%

Proteome signatures of reductive stress cardiomyopathy

Sunny

Parsawar

Jones

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…These pathways can also be used to target genes that might be involved in pathogenesis of atrial fibrillation and can be used as therapeutic targets and potential biomarkers. Biomarkers for atrial fibrillation are already being identified [ 129 , 130 ] and could be useful in clinical risk assessment and outcomes for individuals with atrial fibrillation.…”

Section: Conclusion Challenges and Future Directionsmentioning

confidence: 99%

Are Interactions between Epicardial Adipose Tissue, Cardiac Fibroblasts and Cardiac Myocytes Instrumental in Atrial Fibrosis and Atrial Fibrillation?

Krishnan

Chilton

Raman

et al. 2021

Cells

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Atrial fibrillation is very common among the elderly and/or obese. While myocardial fibrosis is associated with atrial fibrillation, the exact mechanisms within atrial myocytes and surrounding non-myocytes are not fully understood. This review considers the potential roles of myocardial fibroblasts and myofibroblasts in fibrosis and modulating myocyte electrophysiology through electrotonic interactions. Coupling with (myo)fibroblasts in vitro and in silico prolonged myocyte action potential duration and caused resting depolarization; an optogenetic study has verified in vivo that fibroblasts depolarized when coupled myocytes produced action potentials. This review also introduces another non-myocyte which may modulate both myocardial (myo)fibroblasts and myocytes: epicardial adipose tissue. Epicardial adipocytes are in intimate contact with myocytes and (myo)fibroblasts and may infiltrate the myocardium. Adipocytes secrete numerous adipokines which modulate (myo)fibroblast and myocyte physiology. These adipokines are protective in healthy hearts, preventing inflammation and fibrosis. However, adipokines secreted from adipocytes may switch to pro-inflammatory and pro-fibrotic, associated with reactive oxygen species generation. Pro-fibrotic adipokines stimulate myofibroblast differentiation, causing pronounced fibrosis in the epicardial adipose tissue and the myocardium. Adipose tissue also influences myocyte electrophysiology, via the adipokines and/or through electrotonic interactions. Deeper understanding of the interactions between myocytes and non-myocytes is important to understand and manage atrial fibrillation.

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Identification of Potential Crucial Genes in Atrial Fibrillation: A Bioinformatic Analysis

Cited by 2 publications

References 24 publications

Proteome signatures of reductive stress cardiomyopathy

Proteome signatures of reductive stress cardiomyopathy

Are Interactions between Epicardial Adipose Tissue, Cardiac Fibroblasts and Cardiac Myocytes Instrumental in Atrial Fibrosis and Atrial Fibrillation?

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