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 | |
miR-33 | 1. Targets genes involved in HDL metabolism. Preclinical models in which anti-miR-33 was delivered for up to 12Â 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 | |
miR-146 | Pathogenesis and clinical manifestation of atherosclerosis | CD40L, IRAK1, IRAK2, TLR4, TRAF6 | Â | |
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 | |
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. | |
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 | Â | |
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 | |
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 | |
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 | Â | [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 | Â | |
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 | Â | [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 | Â | |
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 |