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Table 1 Mechanisms, clinical relevance, targets and development of microRNA-based therapeutics by companies

From: Epigenetic associations in relation to cardiovascular prevention and therapeutics

 

Mechanisms and clinical relevance

Target(s)

Development of microRNA-based therapeutics by companies

References

miR-208

1. Inhibition of miR-208a prevents cardiac remodeling

2. Role in cardiac fibrosis not yet fully identified

p21

x

[10, 107]

miR-33

1. Targets genes involved in HDL metabolism. Preclinical models in which anti-miR-33 was delivered for up to 12 weeks have shown no adverse effects of the approach (assessed by liver enzymes, plasma cytokine levels, blood chemistry panels, blood counts, body weight)

2. Directly target macrophages and cause a regression of atherosclerosis

ABCA1, ABCG1, AMPK alpha, CPT1A, CROT, HADHB, IRS2, NPC1, PRKAA1, SREBP-1

Anti-miR oligonucleotide against miR-33a/b for treating atherosclerosis and dyslipidemia

[156, 160, 179]

miR-146

Pathogenesis and clinical manifestation of atherosclerosis

CD40L, IRAK1, IRAK2, TLR4, TRAF6

 

[180, 181]

miR-15 family (including miR-15, miR-16, miR-497)

Associated with cell cycle arrest and survival by regulating anti-apoptotic and cell cycle genes

CARM1

Anti-miR towards miR-15 for post-myocardial infarction remodeling of the heart. An 8-mer (nucleotide) directed against the seed region of the miR-15 family: more effective in the derepression of target genes than the previously used LNA-modified 16-mer

[161, 162]

miR-23a, miR-23b, miR-24, miR-195, miR-214

Overexpression of these microRNAs causes hypertrophy in human cardiomyocytes

CDC42 (miR195)

anti-miR towards miR-195 for post-myocardial infarction remodeling of the heart.

[161–163]

Overexpression of miR-195 in the heart is a sufficient cause for heart failure

Transgenic miR-195 mice may develop dilated cardiomyopathy

miR-133

Overexpression of miR-133 inhibits cardiac hypertrophy

SP1

 

[163, 164]

miR-34

The response of the heart to stress, including myocardial infarction, leads to an upregulation of miR-34. Involved in cardiac hypertrophy and fibrosis

SIRT1

LNA-modified anti-miR against miR-34a aimed at improving systolic pressure and increasing angiogenesis

[165]

miR-29

miR-29 is implicated in cardiac fibrosis and is downregulated after myocardial infarct and after cardiac injury

LPL (miR-29a)

Development of a pro-miR to target multiple components of the fibrosis pathway

[166]

DNMT3B (miR-29b)

miR-21

miR-21 levels in cardiac fibroblasts lead to a decrease in its target mRNA, sprouty-1 (Spry1), a negative regulator of ERK-MAP kinase activity, as well as fibroblast growth factor-2 (FGF2) secretion

BCL-2, PDCD4,

ASO to miR-21 in order to elevate Spry1 expression, to reduce FGF2, and therefore to decrease fibroblast growth

[167–169]

PPARalpha,

PTEN, TPM1, TLR4

Anti-miR-21 may help treat a variety of fibrotic conditions, including cardiac fibrosis

miR-155

miR-155 has been implicated in viral myocarditis. An LNA-anti-miR directed against murine miR-155 reduced myocardial damage during myocarditis

AT1R, ETS-1, MLCK, BCL-2, ETS-1, FADD, HBP1, MAP3K10

x

[13, 170–173]

The inhibition of endogenous miR-155 has clinical benefit for both cardiac hypertrophy and heart failure

miR-145

Genetic deletion of miR-145 results in excessive remodeling of the right ventricle and decreasing blood pressure. After vascular injury, the cytoskeleton of smooth muscle cells is modulated by a downregulation of miRNA-145

JAM-A

x

[172]

miR-221, miR-222

Proliferation of smooth muscle cells is partially enhanced by an increase in endogenous miRNA-221 and miRNA-222 levels

c-Kit, eNOS, ETS-1, PAK1, p27, p57, STAT5A

 

[163]

miR-126

As atherosclerosis develops, the inflammation of vessel walls is enforced by a downregulation of miRNA-126 promoting the expression of VCAM-1 (vascular cell adhesion molecule) and inducing the production of CXCL12 (C-X-C motif chemokine 12), which in turn leads to the recruitment and adhesion of further inflammatory cells

BCL-2, FOXO3, IRS1

 

[174, 175]

miR-217

When expression of miRNA-217 in atherosclerotic plaques increases, the endothelium disintegrates, which then leads to the inhibition of SIRT1 that causes an acceleration of vascular senescence

SirT1

 

[176]

miR-1

In developing mouse hearts, the overexpression of miR-1 causes decreased cardiomyocyte proliferation and premature differentiation. Experiments with mice suggest that transient downregulation of miR-1 may prove to be of therapeutic benefit to patients suffering from acute myocardial infarction

MLCK, KLF4, MRTF-A, PIM-1

 

[13, 177, 178]

miR-1 negatively regulates key components of calcium signaling pathways and fetal gene activation, making it a vital part of agonist-induced cardiomyocyte hypertrophy in the mouse

  1. ABCA1 ATP binding cassette transporter A1, ABCG1 ATP binding cassette transporter G1, AMPKα AMP kinase subunit-α, AT1R angiotensin II type 1 receptor, BCL-2 B-cell lymphoma 2, CARM1 coactivator-associated arginine methyltransferase 1, CDC42 cell division control protein 42, CPT1A carnitine palmitoyltransferase 1A, CROT carnitine O-octaniltransferase, DNMT3b DNA methyltransferase 3b, eNOS endothelial nitric oxide synthase, ETS-1 E26 transformation-specific sequence 1, FADD Fas-associated death domain-containing protein, FOXO3 forkhead box O3, HADHB hydroxyacyl-CoA-dehydrogenase, IRAK1 interleukin-1 receptor-associated kinase 1, IRAK2 interleukin-1 receptor-associated kinase 2, IRS1 insulin receptor substrate 1, IRS2 insulin receptor substrate 2, HBP1 HMG box-transcription protein 1, JAM-A junctional adhesion molecule-A, LPL Lipoproteinlipase, MAP3K10 mitogen-activated kinase kinase kinase 10, MLCK myosin light chain kinase, MRTF-A myocardin-related transcription factor A, MYL9 myosin light chain 9, NOX4 NADPH oxidase 4, NPC1 Niemann-Pick C1, PAK1 p21/Cdc42/Rac1-activated kinase 1, PDCD4 programmed cell death 4, PPARα peroxisome proliferator-activated receptor-α, PRKAA1 protein kinase, AMP-activated, α 1 catalytic subunit, PTEN phosphatase and tensin homologue, SIRT1 sirtuin 1, SirT1 silent information regulator 1, SREBP-1 sterol regulatory element-binding protein 1, STAT5A signal transducer and activator of transcription 5A, TLR4 toll-like receptor 4, TPM1 tropomyosin 1, TRAF6 TNF receptor-associated factor 6