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Table 3 Dysregulated microRNA in stenotic valves and experimentally modified aortic valve cells

From: Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy

MicroRNA expression Method Patients [reference]
Upregulated: miR-155/BIC/miR155HG, −21 Microarray 5 AS (TAV), 5 TAVn, male subjects [99]
Downregulated: miR-16, −26a, −27a, −30b, −130a, −195, −497 Microarray
qRT-PCR
4 AS (BAV). 5 AI (BAV), male subjects [115]
Upregulated (ANOVA) TAVc vs. TAVn: miR-32*, 127-3e, −145, −483-5p, −572, −574-5p, −663, −671-5p, −1207-5p, −1224-5p, −1469, −2861 #, −3149, −3621
Upregulated (ANOVA) BAVc + R vs. TAVn: miR-466, −572, −671-5p, 1224-5p, −1207-5p, −1469, −2861, −483-5p, −127-3e, −4267, −663, −145, −3621,
Upregulated (ANOVA) TAVn: let-7e, let-7i, −16, 29a#, miR-29c, −30b #, −30d #, −99a, −126, −100, −103, −107, −125b, −151-5p, −451,
Overexpressed in disease (Mann Whitney U analysis): miR-143, −149*, −198, −483-5p, −572, −602, −638, −663, −671-5p, −762, −1207-5p, −1224-5p, −1231, −1275, −1307, −1469, −2861, −3665, −4270
Overexpressed in control (Mann Whitney U analysis): Let-7f, let-7 g, let-7i, miR-16, −25, −26b, −29a#, −29c, −30b, −30c, −30d, −30e, −99a, −100, −101, −106b, −107, −126, −140-5p, −199a-3p, −451, −486-5p, −4324
Microarray
qRT-PCR
3 AS (TAV; 2 male), 5 BAVc +R (3 male), 4 TAVn (DCM patients, 2 males) [116]
Upregulated: miR-30e, −32, −145, −151-3p, −152, −190, −373*, −768-5p
Downregulated: miR-22, −27a, −124-3pre, −125b-1-pre, −141 (PAVICs), −185-pre-, −187, −194*, −211-pre, −330-5p, −370, −486-3p, −449b*, −551a-pre, −564, −566-pre, −575, −585-pre, −622, −637, −648-pre, −1202, −1282, −1469, 1908–1909*, −1972
Microarray
qRT-PCR
19 BAVc (10 female) vs. 17 TAVc (11 female)
PAVICs harvested from 10 porcine hearts [117]
Downregulated: miR-30a, −30b (HAVICs), −30c, −30d, −30e qRT-PCR 10 AS (5/5 male/female, calcific vs. adjacent tissue)
Primary HAVICs from 10 noncalcified human aortic valves [118]
Upregulated (cyclic stretched HAVICs): miR-132, −146a, −212, −486-5p, −941
Downregulated (BAV vs. control and cyclic stretch HAVICs): miR-148a-3p -19b
Downregulated (cyclic stretch HAVICs): miR-19a, −143, −145, −148a-3p, −335*-, −374a*-, −450b-5p, −1197, −1280
MicroRNA-sequencing
qRT-PCR
9 BAVc vs. 5 healthy aortic valves, male subjects
6 cyclic stretch stretched and 6 static HAAVIC samples [87, 119]
Upregulated: miR-21, −34b, −125a-5p, −125b * , −193b, −423-3p, −625*
Downregulated: miR-124*, −184, −185*, −193a-5p, −374b*, −516a-5p, −519e*, −520d-5p, −602 * , −637, −665, −921, −939 *
Microarray
qRT-PCR
Microarray- 5 AS (1 BAV) vs. 5 control valves (2 BAVs), male subjects
qRT-PCR- 20 AS vs. 6 control [114]
Upregulated: miR-29b-1-5p, −99b-3p, −193a-3p, −194-5p, −200b-3p, −505-5p
Downregulated: miR-21-3p, −21-5p, −34a-3p, −146b-5p, −301a-3p, −3663-3p, −513a-5p, −516a-5p, −575, −630, −636, −718, −1972, −3138
Microarray 4 AS vs. 4 control, male subjects [120]
Upregulated: let-7f-5p, let-7i-5p, miR-21-5p, −27a-5p, −27b-3p, −31-5p, −34a-5p, −143-3p, −146b-5p, −199a-5p, −199a-3p, −199b-3p, −216a-5p, −221-3p, −222-3p, −335-5p, −381-3p, −455-3p, −548a-3p, −550a-3p, −1263, −1275, −3124-5p, −3128, −3178, −3197
Downregulated: miR-1, −16-5p, −17-5p, −18a-5p, −18b-5p, -19b-3p, −20a-5p, −20b-5p, −30d-5p, −30e-5p, −92a-3p, −93-5p, −99a-5p, −103a-3p, −106a-5p, −106b-3p, −107, −122–5p, −124-3p, −125b-2-3p, −128-3p, −133a-3p, −133b, −139-5p, −140-3p, −149-5p, −181a-2-3p, −182–5p, −185-5p, −191-5p, −192–5p, −194-5p, -197-3p, −200c-3p (↑qRT-PCR), −206, −214-3p, −320a, −320b, −320c, −324-3p, −328-3p, −339-3p, −339-5p, −378a-3p, −378a-5p, −378c, −422a, −425-5p, −451a, −486-3p, −486-5p (no difference in qRT-PCR), −491-5p, −500a-3p, −500a-5p, −501-3p, −502-3p, −532–5p, −532-3p, −574-3p, −625-5p, −629-5p, −652-3p, −664-5p, −665, −766-3p, −885-5p, −933, −939-5p, -1180-3p, −1202, −1207-5p, −1225-5p, −1246, −1271-5p, −1287-5p, −2110, −1973, −3162–5p, −4253, −4284
Microarray
qRT-PCR
Microarray- 15 AS (9male) vs. 16 control (12 male)
qRT-PCR 36 (25 male) vs. 16 (11 male) [121]
SAM: Upregulated: (FO/VL): miR-187 $, −217 T , −374a; (VO/VL): −187, −217; (FO/FL): −187, −769-3p;
SAM Downregulated (FO/VL): miR-139-3p $, −382, −433, −483-3p, −485-3p, −485-5p, −486-3p, −486-5p $ (Up qRT-PCR), miR-543, −549 (Up qRT-PCR), miR-923, −1237 (Up qRT-PCR), miR-1244; (VO/VL): miR-139-3p, −192 $, −411, −486-3p, −486-5p, −518e:9.1, −548o, −647, −654-3p, −923, −1244, −1290, −1300; (FO/FL): miR-486-3p, −486-5p, −923, −1244; (FO/VO): miR-485-3p (side dependent), miR-485-5p (side dependent); (FL/VL): miR-370 $ (side dependent)
Additional analysis- Downregulated (VO/VL): miR-192 (previously found as a shear-sensitive miRNA)
Additional 15 miRNAs, chosen based on fold change and importance in other data sets: Upregulated (FO/VL; qRT-PCR): miR-15a, −29c (down qRT-PCR), miR-106b, −126, −148a $, −186, −365, −424 T, −495 (down qRT-PCR); Downregulated (FO/VL; qRT-PCR): miR-10a, −214, −615-5p (unchanged in qRT-PCR), miR-663b (Up qRT-PCR), miR-92b (Up qRT-PCR); Unchanged: miR-92a (Up qRT-PCR)
Microarray
qRT-PCR
HAVECs
from healthy noncalcified valves [87, 122]
SAM: (13 human shear-responsive and side specific out of 24 unique side-specific) miRNAs: miR-100 (Up F/V qRT-PCR, miRNA array), miR-150, −181a (Up F/V qRT-PCR, miRNA array), miR-181b (Up F/V qRT-PCR, miRNA array), miR-199a-3p (Up F/V qRT-PCR, miRNA array), miR-199a-5p (Up F/V qRT-PCR, miRNA array), miR-199b-3p, −214 (Up F/V qRT-PCR, miRNA array), miR-223, −455-3p, −523-star, −618, −708
Additional analysis: Upregulated F/V: miR-130a; miR-192 T, −486-5p *
Microarray
qRT-PCR
FISH
PAVECs
from healthy noncalcified valves [122, 123]
FISH in situ hybridization in cryosections of porcine aortic valve: miR-486-5p- trend for increased staining on the fibrosa side
Upregulated F vs. V at total (mature and pre-miR forms) miRNA level: miR-100 $, −130a $ (homologous to human miR-130a-3p), −181a $ (homologous to human miR-181a-5p), −181b $ (homologous to human miR-181b-3p), −199a-3p $, −199a-5p $, −214 $ (homologous to human miR-214-3p)
Upregulated F vs. V at the mature miRNA level: miR-181a T , −199a-5p * , −199a-3p T , −214 $
Upregulated FO/FL*, VO/VL, FO/VL*, FO/VO*, FO/fresh valve*: mir-214 (side- and shear-dependent)
Microarray qRT-PCR
  1. Legend: AS- aortic valve stenosis; AI- aortic insufficiency; BAVn- healthy noncalcified bicuspid aortic valve; BAVC- stenotic calcified bicuspid aortic valve; BAVc + R- stenotic bicuspid valves in which a raphe was visible; BIC- B-cell receptor inducible, miR155 host gene; DCM dilated cardiomyopathy; HAVECs- human aortic valve cells; HAVICs- human aortic valve interstitial cells; PAVECs- porcine aortic valve cells; FO-fibrosa, oscillatory shear stress; FL- fibrosa, laminar shear stress; FISH- fluorescent in situ hybridization; qRT-PCR- quantitative real time polymerase chain reaction; SAM-Significance of Microarray Analysis; TAVc- calcified stenotic tricuspid aortic valve; TAVn -noncalcified tricuspid aortic valve; VL- ventricularis, laminar shear stress; VO- ventricularis, oscillatory shear stress; miRs- higher expression in TAVc vs. BAVc; miRs designated in bold- miRs evaluated by qRT-PCR. $statistically significant, qPCR of additional miRNAs yielded miR-148a as shear-sensitive (not found in SAM); Ttrend toward significance; #miRNA with similar expression profile in both diseased groups when compared to healthy aortic valves