Yiu, C. H. K. | bioRxiv Science

bioRxiv2024

Atrial Proteomic Profiling Reveals a Switch Towards Profibrotic Gene Expression Program in CREM-IbΔC-X Mice with Persistent Atrial Fibrillation

BackgroundOverexpression of the CREM (cAMP response element-binding modulator) isoform CREM-Ib{Delta}C-X in transgenic mice (CREM-Tg) causes the age-dependent development of spontaneous AF. PurposeTo identify key proteome signatures and biological processes accompanying the development of persistent AF through integrated proteomics and bioinformatics analysis. MethodsAtrial tissue samples from three CREM-Tg mice and three wild-type littermates were subjected to unbiased mass spectrometry-based quantitative proteomics, differential expression and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. ResultsA total of 98 differentially expressed proteins were identified. Gene ontology analysis revealed enrichment for biological processes regulating actin cytoskeleton organization and extracellular matrix (ECM) dynamics. Changes in ITGAV, FBLN5, and LCP1 were identified as being relevant to atrial fibrosis and remodeling based on expression changes, co-expression patterns, and PPI network analysis. Comparative analysis with previously published datasets revealed a shift in protein expression patterns from ion-channel and metabolic regulators in young CREM-Tg mice to profibrotic remodeling factors in older CREM-Tg mice. Furthermore, older CREM-Tg mice exhibited protein expression patterns that resembled those of humans with persistent AF. ConclusionsThis study uncovered distinct temporal changes in atrial protein expression patterns with age in CREM-Tg mice consistent with the progressive evolution of AF. Future studies into the role of the key differentially abundant proteins identified in this study in AF progression may open new therapeutic avenues to control atrial fibrosis and substrate development in AF. Graphical abstractGraphical abstract summarizing key findings of this paper. The atrial proteome in 9-month-old CREM- Tg mice with chronic persistent AF (perAF) was compared with age-matched WT littermates. In addition, proteome changes in these old CREM-Tg mice were compared with proteome changes previously identified in young CREM-Tg mice with paroxysmal AF (pAF). Moreover, an interspecies comparison was performed between old CREM-Tg mice and human patients with perAF. The major findings are that in pAF, key changes were identified in proteins involved in metabolism, energy production, DNA synthesis, and cell proliferation and growth. On the other hand, in mice and humans with perAF, key changes were found in the expression of proteins involved in collagen production, extracellular matrix remodeling, actin cytoskeleton organization, and tissue repair. O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/575097v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@603dbaorg.highwire.dtl.DTLVardef@74a168org.highwire.dtl.DTLVardef@110b834org.highwire.dtl.DTLVardef@ad96e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

Interleukin 11-induced microRNAs as functional mediators and circulating biomarkers of cardiac fibrosis

BackgroundCardiac fibrosis can be triggered by several pathologies, including ischemic heart disease and aortic stenosis (AS). Cardiac fibrosis is brought about by uncontrolled extracellular matrix (ECM) deposition by myofibroblasts. Interleukin-11 (IL-11) has been firmly demonstrated to be a major trigger of multi-organ fibrosis. However, the molecular mechanisms underpinning IL-11-induced fibrosis requires further characterisation. Recent studies indicate that microRNA (miRNA) dysregulation contributes to the pathogenesis of cardiac fibrosis and can be targeted therapeutically. In this study, we explored the hypothesis that miRNAs act as downstream effectors of IL-11-induced cardiac fibrosis. Moreover, we investigated the translational potential of IL-11-regulated miRNAs as circulating biomarkers of cardiac fibrosis in AS patients. Methods and ResultsUsing computational approaches, we identified miRNA-497-5p and miRNA-27b-5p as potential new downstream profibrotic effectors of IL-11 in fibroblasts. We next confirmed that both miRNAs increased in healthy rat CF stimulated with IL-11 and in CF derived from post-infarction failing hearts. At the functional level, miRNA-497-5p and miRNA-27b-5p inhibition indirectly reduced the mRNA expression of collagen 1 (Col1a1). Conversely, transfection of CFs with mimics for each of the two miRNAs promoted fibroblast-to-myofibroblast transition and increased Col1a1 levels. We provided evidences that miRNA-27b-5p and miRNA-497-5p converge to promote hypoxia-inducible factor 1 signalling, by targeting its regulator EGLN (PHD) family members. The clinical relevance of our findings was confirmed using left ventricle (LV) specimens obtained from surgical patients with AS. The miRNA-27b-5p and miRNA-497-5p measured in the LV, peripheral plasma and plasma extracellular vesicles correlated with the severity of LV fibrosis, indicating these miRNAs potential as new circulating biomarkers of cardiac fibrosis. ConclusionsIn this study, we have newly identified the potential value of miRNA-27b-5p and miRNA-497-5p as actionable biomarkers of the profibrotic response to IL-11 in the heart. Future studies should validate the translational potential of the miRNAs as new clinical biomarkers and therapeutic targets.

molecular biology↗