title: 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.
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A & M Health Science Center, Scott & White, Central Texas Veterans Health Care System, Temple, Texas 76504, USA.
authors.forename: Chuanyu
authors.initials: C
authors.lastname: Wei
authors.forename: Il-Kwon
authors.initials: IK
authors.lastname: Kim
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Samantha
authors.initials: S
authors.lastname: Jayasinghe
authors.forename: Nayeon
authors.initials: N
authors.lastname: Hong
authors.forename: Giovanna
authors.initials: G
authors.lastname: Castoldi
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Sudhiranjan
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008955:Models, Cardiovascular; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
chemical_list: C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D024042:Collagen Type I; D020672:I-kappa B Proteins; C556274:MIRN26 microRNA, rat; D035683:MicroRNAs; C543693:Mirn26 microRNA, mouse; D050505:Mutant Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D000072000:NF-KappaB Inhibitor alpha