Table 4.
MicroRNAs described for their role in structural remodelling
| MiRNA in AF | Target(s) in AF | Experimental Model | Function | Reporting Studiesa | ||
|---|---|---|---|---|---|---|
| miR-21 | ↑ | Pitx2c [136] | ↓ | Pig ATP model, HL-1 cells | Upregulation in AF was correlated with decreased PITX2C protein. Its overexpression in vitro decreased mRNA and protein while inhibition with antimiR-21 had opposite effects. | [17, 18, 40, 44, 53, 56, 59, 74, 96–98, 136] |
| SPRY1 [17] Spry1 [18] | ↓ | 5 valvular AF, 5 SR patients, TG mice expressing Rac1, neonatal rat fibroblasts, in vivo inhibition in an ischemic rat/mice model. | Upregulation in LAA from AF patients and in an ischemic mice model was seen and correlated with increased fibrotic content and a decrease of SPRY1. Administration of Ang-II induced an increase of CTGF and miR-21 in cardiac fibroblasts while Spry1 decreased.. In vivo inhibition with antagomir-21 or a 15-mer-LNA based antimiR-21 suppressed the fibrotic response and prevented increased AF susceptibility. | |||
| STAT3b [98] | ↑ | Sterile rat pericarditis model with ATP, in vivo inhibition in pericarditis rat, neonatal and adult rat atrial fibroblats | Pericarditis in rats increased AF susceptibility and fibrosis and upregulated IL1B, IL-6, TGFB, TNFa, STAT3 and miR-21. In vitro inhibition of miR-21 suppressed STAT3 phophorylation, Col1A1 and Col3A1 mRNA, while overexpression had opposite effects. In vivo inhibition with antagomir-21 decreased STAT3 phosphorylation, fibrosis and AF vulnerability, | |||
| Smad7 [97] | ↓ | Rabbit ATP model, in vivo forced expression in rabbits, rat cardiac fibroblasts | Upregulation of TGF-β1 mRNA and protein in ATP rabbits correlated with increased miR-21 and decreased Smad7. In vivo pre-treatment with miR-21 inhibitor restored Smad7 and prevented a decrease in collagen I/III mRNA and protein. MiR-21 directly targeted Smad7. | |||
| mir-26a | ↓ | TRPC3 [86] | ↑ | VTP canine model with CHF, ATP goat model, canine and rat cardiac fibroblasts | Downregulation in isolated LA fibroblast form AF dogs correlated with increased TRPC3 protein. Its overexpression in vitro suppressed TRPC3 protein and fibroblast number, while inhibition had opposite effects. Administration of NFAT-blocker increased miR-26a/b in vitro. MiR-26a directly targeted TRPC3. | [16, 46, 68–70, 86] |
| miR-29b | ↓ | COL1A1, COL3A1, FBN [103] | ↑ | RA from 17 AF, 19 SR patients, VTP canine model with CHF, canine fibroblasts, in vivo inhibition in mice, human AF plasma samples | Downregulation was seen in RA tissue of AF patients and LA tissue and fibroblasts from VTP dogs. Plasma levels of AF patients were also lower. VTP dogs demonstrated increased COL1A1, COL3A1 and FBN in fibroblasts. MiR-29b inhibition in vitro with miR-29b sponge increased mRNA levels and protein of those ECM components while overexpression had opposite effects. In vivo inhibition with miR-29b sponge in mice increased atrial COL1A1 and tissue collagen content. | [30, 103] |
| miR-30a | ↓ | Snail 1[104] | ↑ | Rabbit ATP model, cardiac rat fibroblasts | Downregulation in ATP rabbits correlated with increased Snail1 and Periostin mRNA and protein levels. MiR-30a overexpression xin vitro suppressed snail1 and periostin mRNA and protein, while inhibition increased their expression. MiR-30a directly targeted Snail1. | [104, 137] |
| miR-133 | ↓ | TGF-β1 [107] | ↑ | 19 AF patients, with or without nicotine abuses, canine model with nicotine administration, canine atrial fibroblasts | Downregulation in dogs and canine fibroblasts correlated with increased nicotine concentration. Nicotine usage was also associated with downregulation in human RA. MiR-133 overexpression in vitro decreased TGF-β1 protein and collagen content, while inhibition increased TGF-1 and collagen content. Nicotine administration in vitro decreased miR-133. MiR-133 directly targeted TGF-β1. | [44, 46, 107, 137] |
| miR-146b | ↑ | TIMP-4[108] | ↓ | 30 parAF, 17 SR patients, mice cardiac fibroblasts | Upregulation in AF correlated with decreased TIMP-4. MiR-146b in vitro overexpression decreased TIMP-4, which could be prevented by inhibition. A downregulation of TIMP-4 was associated with increased MMP-9 and collagen content. MiR-146b directly targeted TIMP-4. | [37, 44, 53, 108, 109] |
| miR-208a/b | ↑ | Thrap1, myostatin GATA4 [111] | ↓ | Mice pressure overload model, rat cardiomyocytes, TG and KO mice | MiR-208a KO mice developed spontaneous AF. TG mice overexpressing miR-208a had reduced Thrap1 and myostatin protein levels and hypertrophic growth while KO induced an increase. MiR-208a/b directly targeted Thrap1, myostatin and miR-208 targeted GATA4. | [31, 53, 58, 62, 71, 74, 111, 114] |
| miR-208a/b | ↑ | Sox5, Sox6 [58] | ↓ | 4 permAF, 2 SR patients, human cardiac myocytes, HL-1 cells | Upregulation in AF correlated with decreased Sox5, Sox6 and increased Myh7. Overexpression of miR-208b in vitro suppressed Sox6 and increased Myh7. Overexpression of miR-208a in vitro suppressed Sox5 and moderately increased Myh7. | [31, 53, 58, 62, 71, 74, 111, 114] |
| miR-590 | ↓ | TGF-βR2 [107] | ↑ | 19 AF patients, with or without nicotine abuses, canine model with nicotine administration, canine atrial fibroblasts | Downregulation in dogs and canine fibroblasts correlated with increased nicotine concentration. Nicotine usage was also associated with downregulation in human RA. MiR-590 overexpression in vitro decreased TGF-βR2 protein and collagen content, while inhibition increased TGF-β2 and collagen content. Nicotine administration in vitro decreased miR-590. MiR-590 directly targeted TGF-βR2. | [107, 114] |
aStudies reporting about the specific miRNA in AF. These include both explorative and functional studies in tissue and plasma and may present conflicting data regarding upregulation or downregulation of the miRNA
bNot a direct target of the miRNA
Abbreviations: AF atrial fibrillation, Ang-II angiotensin-II, APD action potential duration, ATP atrial tachypacing, CHF congestive heart failure, CTGF connective tissue growth factor, FBN fibrillin, FKBP5 FK506 binding protein 5, KO knockout, LA left atrium, MMP-9 Matrix metallopeptidase 9, MVS mitral valve stenosis, NFAT nuclear factor of activated T-cells, permAF permanent/chronic AF, PITX2 paired-like homeodomain transcription factor 2, RA right atrium, Smad7 decapentaplegic homologue 7, SPRY1 sprouty RTK signalling antagonist 1 gene, SR sinus rhythm/controls, STAT3 signal transducer and activator of transcription 3, TG transgenic, TGF-β1 transforming growth factor-β1, TGF-βR2 transforming growth factor β receptor type 2, THRAP1 thyroid hormone-associated protein 1, TIMP-4 Metalloproteinase inhibitor 4, TRPC3 transient receptor potential canonical-3, VTP ventricular tachypacing