Table 4 Functional analysis of dysregulated microRNAs in stenotic aortic valves and experimentally modified aortic valve cells

↓ 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*, ↓BMP4^T; ↑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

[131, 132]

↑ 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

[131, 132]

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.

[132, 133]

↑ 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]