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

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
[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]
  1. Legend: ALP- alkaline phosphatase; ANG II- angiopoietin 2; ApoE- apolipoprotein E; AS- aortic valve stenosis; ASH2l- ASH2 like histone lysine methyltransferase complex subunit; AV- aortic valve; AVSc- aortic valve sclerosis; BAVc- stenotic calcified bicuspid aortic valve, BAVc + R- stenotic calcified bicuspid valves in which a raphe was visible; BGLAP/OCN- osteocalcin; BMP2/4- bone morphogenetic protein 2/4; CASP3- caspase 3;CCL4- C-C motif chemokine ligand 4; CXCL2- C-X-C motif chemokine ligand 2; CXCL12- C-X-C motif chemokine ligand 2; EFNA1- Ephrin A1; HAVICs- human aortic valve interstitial cells; HDAC5- histone deacetylase 5; IGF1- insulin like growth factor 1; IGF2- insulin like growth factor 2; IKBKB- inhibitor of kappa light polypeptide gene enhancer in B-Cells, Kinase Beta; IL1β- interleukin 1 beta; IL8- interleukin 8; JAG2- Jagged 2; LNA-miR- locked nucleic acids resistant to exo- and endonucleases resulting in high stability in vivo and in vitro and increased target specificity; KLF2- Kruppel like factor 2; LS- laminar shear stress; NF-κB- nuclear factor kappa-light-chain-enhancer of activated B cells; NOX4- NADPH Oxidase 4; MMP2/9/14/16- matrix metalloproteinase 2/9/14/16; MYLK- myosin light chain kinase; OGT- O-linked N-acetylglucosamine; SPP1OPN- osteopontin; OS-oscillatory shear stress; PAVCs- porcine aortic valve; PRND- Prion Protein 2 (Dublet); RUNX2- Runt related transcription factor 2; SMAD1/3/5/7- SMAD Family Member 1/3/5/7; SOD- superoxide dismutase; SP7/OSX- osterix; TAVc- stenotic calcified tricuspid aortic valve; TGFBR2 –transforming growth factor beta receptor 2; THBS1- thrombospondin 1; TWIST1- Twist family BHLH transcription factor 1; VCAM1- vascular cell adhesion molecule 1; *Statistically significant; T trend toward significance