Table 2.
ncRNAs and TGF-β/Smad signaling in cardiac fibrosis.
| Non-coding RNAs | Effect(s) | Modulation | Targets Smads | Signaling pathway | Model | References |
|---|---|---|---|---|---|---|
| miRNA | ||||||
| miR-25 | Antifibrosis | Downregulated | COL1/COL3 Smad3 |
miR-25 → ↓ TGF-β1 → ↓collagen I/III |
Transaortic constricted mice | (120) |
| miR-133 | Antifibrosis | Downregulated | EP300 COL4A1, FN1 Smad2 |
↑miR-133a → ↓ phosphorylation of p-ERK1/2 and p- Smad2 → EP300/ ↓ TGF-β1/CTGFL/↓fibronectin/COL4A1 → ↓ cardiac fi/ COL4. |
Streptozotocin-induced diabetic in mice | (121) |
| Snai1 Gata4, Mef2c, and Tbx5 Mesp1 |
GMT/miR-133/ Snai1-induced aMHC-GFP → ↑ cardiac reprogramming → ↓CF |
Mouse embryonic fibroblasts | (122) | |||
| miR-433 | Profibrosis | Upregulated | TGF-β1, ERK, p38 kinase, and Smad3 |
Suppress AZIN1 and JNK1/ /TGF-β1, ERK, p38 kinase, and Smad3 → ↑ cardiac fibrosis. |
MI/mice; NRCFs | (123) |
| miR-29b-3p miR-29c-3p |
Antifibrosis | Upregulated | TGF-β2, Mmp2 | miR-29b/miR29c → ↑ MIF → ↓ COL1A1, COL3A1/α-SMA,/ Smad3 → ↓ cardiac fibrosis. |
(AngII)-infused mouse myocardium Mif-knockout (Mif-KO) mice | (124) |
| mRNA 3′-UTR Col 1a1, Col 5a3, and Col 4a2 Smad3 |
↓TGF-β /Smad3 → ↓collagen I, III, fibronectin → ↓CF | AngII-triggered cardiac fibrotic event in mice Mouse CFs | (125) | |||
| Fibrillins and elastin | Altered the secretion of growth factors and cytokines, including MMP, IGF-1, LIF, and PTX-3 ↓ TGF-β → ↓CFs |
AngII (1.46 mg/kg/d, 14 d)-infused mouse myocardium | (20) | |||
| miR-21 | Profibrosis | Upregulated | ↓ Smad7 | ↑miR21 → ↑TGF-β1 → ↑myocardial fibrosis by inhibiting Smad7 | Fibro TAC/mouse | (126) |
| ↓Smad2/3 ↓ TGF-β R III//p-Smad3 |
Activate sprouty homolog ↑1/ERK-MAP kinase ↑TGF-β1/Smad2/3 signaling pathway → ↑CF |
MI/mouse | (127) | |||
| ↑PTEN Spry1 |
Activate osteopontin/PTEN and ↓Smad7 → ↑CF |
AngII/mousesis | (79) | |||
| miR-19a-3p/19b-3p | Antifibrosis | Upregulation | TGF-β R II | miR-19a-3p/19b-3p → ↓ TGF-β → ↓ phosphorylation of Smad2 and Akt → ↓CF |
Human Cardiac Fibroblasts (HCF) | (128) |
| miR-24 | Antifibrosis | Upregulated | Furin–TGF-β pathway. | ↓ TGF-β-p → ↓ Smad2/3 → ↓ Furin → ↓ col-1/α-SMA → ↓CF |
Mouse model of MI | (129) |
| Smad2/3 | ↓ TGF-β-p → ↓ Smad2/3 → ↓CF | Mouse model of MI | (130) | |||
| ↓JP2(junctophilin-2) | miR-24 regulates excitation-contraction (E-C) coupling by targeting JP2 |
Aortic stenosis rat model | (131) | |||
| miR-26a | Profibrosis | Upregulated | Col1α2, Col1a1 | Regulation of nuclear factor nuclear factor κB and progress of fibrosis |
AngII/NRCFs | (129) |
| CTGF/Smad1 | BMP/Smad1 signaling | TAC/IkBa tg mouse | (132) | |||
| miR-15 family six miRs (miR-15a, miR-15b, miR-16, miR-195, miR-497, miR-322) | Antifibrosis | Upregulated | ↓TGF-βR I | ↓ TGF-β pathway ↓ Cardiac remodeling and fibrosis ↑cardiac function |
Adult mice under ischemia–reperfusion (I/R) injuries | (133) |
| p38, endoglin, Smad3/7 | ↓ECM remodeling in the overloaded heart ↓ TGF-β pathway |
TAC/mouse | (134) | |||
| miR-1 | Antifibrosis | Downregulated | ↓Smad3 | ↓ TGF-β pathway → ↓ Smad3 → ↓ CF | Mouse models of AngII-induced hypertension | (125) |
| miR-1 | Antifibrosis | Downregulated | Fibullin | Activate ↑fibullin-2/MAPK → ↓CF | AAB/rat | (135) |
| miR-101a | Antifibrosis | Downregulated | c-Fos Smad3 | miR-101 → ↓c-Fos/TGF-β1 pathway → ↓p-Smad3 → ↓CF | Healthy male Sprague–Dawley rats (weight, 200–250 g) and C57BL/6 Mice | (136) |
| TGF-βR1 | ↓TGF-βR I ↓ MAPK → ↓CF | AngII, MI/rat MI, hypoxia/rat NRCFs and MI rat | (137) | |||
| miR-34a | Profibrosis | Upregulated | Smad4 | ↑TGF-β1/Smad4 | MI, male C57BL/6 mice (12 weeks of age and a weight of 25–30 g) | |
| Suppress PNUTS | Age-triggered expression of miR-34a → ↓PNUTS → inducing DNA damage responses along with telomere attrition → ↑CF | Aging, MI/mice, human | (138) | |||
| miR-122 | Antifibrosis | Downregulated | Smad4↓ | ↓TGF-β1 → ↓CF | AS (aortic stenosis patients)/human | (139, 140) |
| miR-378 | Antifibrosis | Downregulated | ↓Grb2/TGF /pSmad2/3, IGF1 receptor↓ Activate RTK Integrin β3↓ ↓cFos, ↓c-Jun and Ras |
miR-378 → ↓TGF-β1–dependent paracrine mechanisms → ↓fibroblast migration and differentiation |
AngII, TAC/mouse; NRCFs | (141) |
| miR-208a | Profibrosis | Upregulated | ↑Smad3/4, ↑endoglin ↑β-MHC |
↑miR-208a → ↑TGF-β1 → ↑ endoglin/collagen I → ↑ CF | Aortacaval shunt/rat TAC mouse and RCFs | (142) |
| ↓Thrap1, myostatin ↑ Endoglin |
Induced cardiac fibrosis and cardiac fiand card proliferation | TG mouse | (143) | |||
| miR-145 | Antifibrosis | Upregulated | TGF-βR II | miR145 acts toward suppression of TGF-β-dependent extracellular matrix accumulation as well as fibrosis | Smooth muscle cells | (144) |
| Smad2 | Smad2 Alters macrophage sensitivity to TGF-β |
AngII/mouse | (145) | |||
| miR-125b | Profibrosis | Upregulated | ↓Apelin, p53 | miR-125b → Inhibition of p53 → induces fibroblast proliferation | TAC, AngII/mouse | (146) |
| miR-22 | Profibrosis | Upregulated | Mimecan/osteoglycin (OGN) | miR-22 → ↓ OGN in age-associated cardiac alterations, including cardiac fibrosis | Aging/mouse; NRCFs | (147) |
| Smad4 TGF-βR I in CFs | ↑ TGF-β1 → ↑ complex (Smad2/3/4) → ↑ CF | MI mice | (148, 149) | |||
| miR-142-3p | Antifibrosis | Downregulated | HMGB1 Smad3 |
miR-142-3p/HMGB1 → ↓ TGF-β1/Smad3 → ↓apoptosis and fibrosis | Mouse cardiomyocyte M6200 cells received treatment with H/R | |
| miR-433 | Profibrosis | Upregulated | AZIN1 JNK1 Smad3 |
↓ AZIN1 → ↑ TGF-β1 → ↑ CF ↓JNK1 → ↑ MAPK kinase (ERK/P38) → ↑ Smad3 → ↑ CF |
Neonatal rat CFs (8-week-old male C57BL/6 mice) | (123) |
| miR-499 | Profibrosis | Upregulated | Acta1, Smads, Fos, Egr1, Egr2 |
↑ MAPK kinase (ERK/P38) /↑ TGF-β1 → ↑CF | Neonatal rat cardiac fibroblasts. (NRCFs) | (143) |
| miR-10a | Profibrosis | Upregulated | ↑Collagen I, collagen III, α-SMA, ↓ Smad7 |
TGF-β1/Smads ↑ Hydroxyproline → ↑cardiac fibrosis and cardiac fibroblast proliferation |
Atrial fibrillation (AF) rat | (8) |
| lncRNAs | ||||||
| lncRNA, Crnde | Antifibrosis | Downregulated | Acta2 α-SMA Smad3 |
Smad3 → ↑ Crnde → ↑rSBEs → ↓ Binding of Smad3 to the Acta2 / α-SMA gene promoter → ↓CF ↑ Cardiac function |
Mouse neonatal cardiac | (150) |
| GAS5 | Antifibrosis | Downregulated | ↓ miR-21/PTEN/MMP-2 | GAS5 → ↓ miR-21 → ↓TGF-β1/Smad2/3 → ↓CF |
ISO/rat; TGF-β1/NRCFs | (151) |
| 5 lncRNAs(n379599, n379519, n384648, n380433, and n410105) | Profibrosis | Upregulated | ↑P-Smad2/3 ↑Elastin, periostin, PAI-1, Snai1, Snai2, FBN1 | TGF-β pathway → ↑cardiac fibrosis | Ischemic cardiomyopathy | |
| Col8A1,Col3A1 fibronection | TGF-β pathway (PAI-1, Snai1, Snai2,/p-Smad2/3) → ↑cardiac fibrosis | ICM/human; mouse CFs | ||||
| lncRNAs CHRF | Profibrosis | Upregulated | miR-489 | CHRF → regulate MyD88 and Smad3 by targeting miR-489 → ↑CF | AngII-treated myocytes Mouse model Human heart failure samples | (81, 152, 153) |
| Circular RNAs | ||||||
| circ_000203 | Profibrosis | Upregulated | MiR-26b-5p BMP/Smad1 |
CircRNA_000203 → ↓ miR-26b-5p(anti-fibrotic) → ↑ Col1a2 /Col3a1/α-SMA CTGF → ↑CF BMP/SMAD1 signaling |
AngII/mouse CFs Diabetic mouse myocardium | (54, 84, 129, 154) |
| CircRNA_010567 | Profibrosis | Upregulated | ↓miR141 TGF-β/Smad pathway |
CircRNA_010567 → ↓miR-141 → ↑ TGF-β1 → ↑Col I/ Col III/α-SMA. → ↑CF |
Diabetic mouse Myocardial fibrosis model |
|
| circRNA–circNFIB | Antifibrosis | Upregulated | miR-433 TGF-β/Smad3 |
↑circNFIB → ↓miR-433 → ↓CF | Mice post-MI cardiac fibroblasts |
|
| circHIPK3 | Pro fibrosis | Upregulated | miR-29b-3p Smad3 |
circHIPK3 → ↓miR-29b-3p → ↑ TGF-β/Smad3 → ↑α-SMA, COL1A1, COL3A1 → ↑CF | AngII-induced cardiac fibrosis | (155) |