NF‐κB mediated miR‐26a regulation in cardiac fibrosis

Abstract

Micro-RNAs (miRNAs) are a class of small non-coding RNAs, recently emerged as a post-transcriptional regulator having a key role in various cardiac pathologies. Among them, cardiac fibrosis that occurs as a result from an imbalance of extracellular matrix proteins turnover and is a highly debilitating process that eventually lead to organ dysfunction. An emerging theme on is that miRNAs participate in feedback loop with transcription factors that regulate their transcription. NF-κB, a key transcription factor regulator controls a series of gene program in various cardiac diseases through positive and negative feedback mechanism. But, NF-κB mediated miRNA regulation in cardiac fibrosis remains obscure. Bioinformatics analysis revealed that miR-26a has targets collagen I and CTGF and possesses putative NF-κB binding element in its promoter region. Here, we show that inhibition of NF-κB in cardiac fibroblast restores miR-26a expression, attenuating collagen I, and CTGF gene expression in the presence of Ang II, conferring a feedback regulatory mechanism in cardiac fibrosis. The target genes for miR-26a were confirmed using 3'-UTR luciferase reporter assays for collagen I and CTGF genes. Using NF-κB reporter assays, we determine that miR-26a overexpression inhibits NF-κB activity. Finally, we show that miR-26a expression is restored along with the attenuation of collagen I and CTGF genes in cardiac specific IkBa triple mutant transgenic mice (preventing NF-κB activation) subjected to 4 weeks transverse aortic banding (TAC), compared to wild type (WT) mice. The data indicate a potential role of miR-26a in cardiac fibrosis and, offer novel therapeutic intervention.

Biomarkers in patients with myocardial fibrosis

“…In cardiac fibroblasts, NF-κB activity can be inhibited by inhibition of miR-26a overexpression, while NF-κB repairs miR-26a expression and leads to CTGF and collagen I gene expression reduction, suggesting a feedback regulatory mechanism. The role of miR-26a indicates a potential therapeutic intervention for cardiac fibrosis [46]. Cardiac infarction and angiotensin II both can reduce the expression of miR-101a and miR-101b (miR101a/b).…”

Role of Exosomes in Myocardial Remodeling

“…90,91 miR-21 and miR26a also regulate the expression of matrix metalloproteinase (MMP)-2, known to be important in extracellular matrix remodeling during hypertrophy. 92,93 miR-26 and miR-133a/b are highly expressed in muscle and heart, but are only expressed in late-stage hypertrophy. miR-133 regulates the IP3 channel receptor gene, leading to prohypertrophic calcium signaling.…”

Role of MicroRNAs in the Trabecular Meshwork

“…84,85 MiR-26 appears to be also anti-fibrotic in the heart by inhibiting collagen I and connective tissue growth factor. 86 Inhibition of the let-7 family leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo. 87 The let-7 family is believed to inhibit fibrosis by repressing expression of collagen genes.…”