From: Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy
Dysregulated microRNA | Source | Role | Reference |
---|---|---|---|
↓ miR-19b | BAVc, HAVICs (cyclic stretch) | MiR-19b mimic (HAVICs) → modulation of osteogenic TGFβ signaling: ↓ TGFBR2, IGF1 (HAVICs under cyclic stretch), relative ↑ SMAD3*/ SMAD5*, ↑ ALP* mRNA | [119] |
↓ miR-26a | BAVC, diseased and healthy HAVICs | MiR-26a mimic (HAVICs) → pro-calcification related genes: ↓ALP*, ↓BMP2*, ↓SMAD1*, ↓BMP4T; ↑RUNX2* ↑SMAD5*; anti-calcification related genes ↑JAG2*↑SMAD7* | [118] |
↓miR-29a/c | BAVc, BAVc +R, TAVc | ↓miR-29a/c (BAVc, BAVc +R, TAVc) → ↑Collagen 1, ↑Collagen 3 | [116] |
↓ miR-30b | BAVc, diseased and healthy HAVICs | MiR-30b mimic (HAVICs) → pro-calcification related genes: ↓SMAD1*, ↓SMAD3*; anti-calcification related genes: ↑JAG2*, ↑SMAD7*, ↓NOTCH1* | [115] |
Calcific AS valves | MiR-30b mimic (HAVICs) → reduce BMP2-induced osteoblast differentiation: ↓ RUNX2, ↓ SMAD1, ↓ CASP3; ↓ ALP activity, ↓BGLAP/OCN | [118] | |
BAVc, BAVc +R, TAVc | ↓miR-30b(c/d) (BAVc, BAVc +R, TAVc) → ↑ RUNX2 | [116] | |
miR-30e | Aortic valves | Injections of antimiR-30e in ApoE−/− mice → ↑ IGF2 (aorta, liver), ↑ OPN* protein expression and ↑ calcium deposition* in aortic valves | [125] |
↑ miR-125b | TAVc/BAVc (5/1), cultured human THP1 macrophages | miRNA-125b transfection (human THP1 macrophages) → ↓ CCL4* | [92] |
↓ miR-141 | BAVc, TAVc, PAVICs | ↓ miRNA-141 (BAVc vs. TAVc) miRNA-141 transfection (PAVECs) → ↓ BMP2, represses TGFβ–triggered PAVIC response to injury and calcification | [117] |
↑ miR-143 | Human and murine model of AVSc | ↑ miR-143 (VICs exposed to oxidative damage in the presence of SOD mimetics and AV explants) With SOD mimetics mediates the pathological valve remodeling (matricellular protein expression αSMA, OPN) in a murine model of AVSc | [126] |
Osteogenic-induced (TGβ1) VICs | C57BL/6 J mice injected with LNA-miR143 after the development of AV thickening (after 4–8 weeks of ANG II infusion that mimic AV remodeling a in AVSc) have reduced AV peak gradient, peak velocity, and velocity-time-interval. in silico target prediction revels miR143 as a regulator of OPN-CD44 axis that mediates calcium deposition via phospho-AKT in HAVICs from patients with noncalcified AVSc | [127] | |
↓ miR-148a-3p | BAVc, cyclic stretch HAVICs | Cyclic stretch (HAVICs) → ↓ miR-148a-3p → ↑ NF-κB → activates NF-κB dependent inflammatory signaling pathways MiR-148a mimic transfection (HAVICs) → ↓ IKBKB; ↓NF-κB signaling, ↓NF-κB target gene expression → ↓ IL1B, ↓ IL8, ↓ MMP1, ↓MMP14, ↓ MMP16 | [119] |
↑ miR-181a | Porcine AV leaflets (cyclic stretch vs. static conditions) | ↑ miR-181a (15% cyclic stretch porcine AV leaflets) → ↓ ALP*, ↓ BGLAP/OCN* | [128] |
↑ miRNA-181b | Aortic valve endothelium | Shear-sensitive miRNA-181b impairs anti-inflammatory signaling in the aortic valve endothelium ↑ miRNA-181b (AVECs in OS conditions) correlates with: ↑ inflammatory adhesion molecules, ↓anti-inflammatory marker KLF2 OS → ↓ predicted miRNA-181b target OGT → decreased binding of OGT to MEF2C → inhibition of MEF2C O-GlcNAc modification | [129] |
miR-187 | HAVECs | Overexpressed miR-187 in vHAVECs → significant decrease in monocyte adhesion in vHAVECs exposed to LS → reduction in inflammatory state | [122] |
↓ miR-195 | BAVc, diseased and healthy HAVICs | MiR-195 mimic transfection (HAVICs) → pro-calcification related genes: ↑BMP2*, ↑RUNX2*; ↑SMAD1*, ↑SMAD3*, ↑SMAD5*; anti-calcification related genes: ↑JAG2*, ↑SMAD7* | [115] |
↓ miR-204 | AS and HAVICs | ↓ miR-204 (AS and BMP2 treated HAVICs) → ↓ RUNX2 miR-204 mimic transfection (BMP2 treated HAVICs) → ↓ ALP* ↓ BGLAP/OCN*, ↓ BMP2 induced RUNX2 mRNA and protein levels | [130] |
Healthy and diseased HAVICs | TGFβ1 and BMP-2 treated HAVICs → ↓ miR-204 → ↑ RUNX2, ↑ SP7/OSX Mir-204 mimic → ↓ RUNX2, ↓ SP7/OSX | ||
↑ miR-214 | Porcine AV leaflets (cyclic stretch vs. static conditions) | ↑ miR-214 (15% cyclic stretch porcine AV leaflets) → ↓ ALP*, ↓ BGLAP/OCN* | [128] |
PAVECs | anti-miR-214 (whole AV leaflets with the fibrosa exposed to OS) → ↑ TGFβ1*, moderate ↑ collagen content, not effect on AV calcification | [123] | |
AS and HAVICs Hypercholesterolemic ApoE−/− murine AS model M1/M2 macrophage | ↑ miR-214 accompanied with valve calcification and M1 macrophage polarization M1 macrophage-derived microvesicles deliver miR-214 to HAVICs → pro-osteogenic differentiation, ↓ TWIST1 → aortic valve calcification intravenous treatment of hypercholesterolemic male ApoE−/− mice with a miR-214 inhibitor → significant suppression of valve calcification, ↑ TWIST1 | [134] | |
miR-483-3p | HAVECs | ↓miR-483-3p (HAVECS subjected to OS) → ↑ ASH2L ↑ miR-483-3p (HAVECS subjected to LS) → ↓ ASH2L | [135] |
↑ miRNA-486 | TGF-β1 and BMP-2 treated HAVICs | TGFβ1 and BMP-2 treated HAVICs → ↑ miR-486 miR-486 mimic (TGFβ1 and BMP-2 treated HAVICs) → ↑ RUNX2, ↑ SP7/OSX | |
Healthy and diseased HAVICs | miR-486 mimic (HAVICs) → ↑α-SMA through modulation of PTEN-AKT pathway, ↑ MYLK →cell aggregation, fibroblast-to-myofibroblast HAVICs transition and calcification nodule formation Prolonged miR-486 treatment (healthy HAVICs) → ↑ collagen I, ↑ MMP2 and ↑ MMP9. | ||
↑ miR-486-5p | HAVECs Porcine ventricularis | ↑ miR-486-5p (HAVECs subjected to LS, porcine ventricularis) → ↑ cell migration, ↓ apoptosis Potential targets: EFNA1 and PRND – role in endothelial-to-mesenchymal transition and oxidative stress | [136] |
miR-1237-3p | Healthy HAVECs porcine aortic valves | differential expression between OS (↓ miR-1237-3p) and LS (↑ miR-1237-3p) miRNA1237-3p mimic → ↓ monocyte binding ↓VCAM1, ↓IL1β in static HAVECs | [137] |
↑ miR-1237-3p (HAVECs subjected to LS) → ↓CXCL2, ↓CXCL12, ↓NOX4, ↓ THBS1 → ↓ inflammation, endothelial dysfunction, valve calcification ↓ miR-1237-3p (HAVECs subjected to OSS) → ↑CXCL2, ↑CXCL12, ↑NOX4, ↑ THBS1 → ↑ inflammation, endothelial dysfunction, valve calcification | [138] | ||
miR-2861 | BAVc, BAVc +R, TAVc | ↑ RUNX2, probably by targeting its inhibitor HDAC5 | [116] |