Table 1.
MicroRNA sequences associated with macrophage ”foam cell” formation and atheroma
| MicroRNA (↑↓) | Macrophage | Stimulus | Target | Outcomes in vitro | Outcomes in vivo | Ref. |
| Lethal: (let)-7g-5p (↓) | Human: THP-1 macrophages | Oxidized low density lipoprotein (oxLDL) | Nuclear factor kappa beta (NF-κB) (canonical and non-canonical pathways) | Inhibits phosphorylation of inhibitor kappa B kinase (IKK-κB and inhibitor (I) κB, downregulates sterol regulatory element binding transcription factor (SREBF2) and upregulates ATP binding cassette (ABC) transporter A1 (ABCA1); reduces expression of mitogen-activated protein kinase kinase kinase 1 (MEKK1), IKK-κ and inhibits IKK-κ phosphorylation | Overexpression of let-7 g in apolipoprotein (apo)E-/- mice fed a high fat diet (HFD) reduces macrophage accumulation and aortic plaque area; let-7 g sponge accelerates aortic macrophage accumulation in the same model | Wang et al[155], 2017 |
| miR-7-5p | Human: THP-1 macrophages | oxLDL ± puerarin | Serine/threonine kinase 11 (STK11) | Mimic significantly decreases cholesterol efflux and promotes cholesterol deposition | - | Li et al[156], 2017 |
| miR-9-5p | Human: THP-1 macrophages | oxLDL | Acyl CoA: Cholesterol acyltransferase (ACAT-1; SOAT1) | Mimic decreases levels of ACAT-1 protein, reduces cholesterol esterification and blocks foam cell formation | - | Xu et al[157], 2013 |
| miR-10a-5p | Murine: ApoE-/- macrophages | Deletion of dicer | - | Mimic rescues defective oxidation of fatty acids in alternatively activated Dicer-deficient macrophages, limiting foam cell formation and inflammation | Levels of hsa-miR-10a are negatively linked to atheroma progression; blockade of miR-10a exacerbates atheroma in apoE-/- mice (HFD) | Wei et al[158], 2018 |
| miR-16-5p (↓) | Murine: RAW 264.7 macrophages | OxLDL | Programmed cell death 4 (PDCD4) | Mimic decreases expression and secretion of pro-inflammatory cytokines (interleukin (IL)-6, Tumour necrosis factor (TNF-α), promotes that of anti-inflammatory IL-10, and suppresses NF-κB expression; inhibitor achieves the reverse | Levels decreased in atheroma in apoE-/- (HFD) | Liang et al[159], 2016 |
| miR-17-5p | Human: THP-1 macrophages | oxLDL | Beclin-1 | Mimic inhibits the enhancement of autophagy and cholesterol efflux induced by interferon-stimulated gene 15 (ISG15) | - | Huang et al[160], 2018 |
| miR-19a-3p | - | - | HMG-Box transcription factor-1 (HBP-1) | - | Serum levels are elevated in atherosclerotic patients, and in aortae susceptible to atherosclerosis. Inhibition decreases atheroma and aortic lipid accumulation in apoE-/- (HFD) mice | Chen et al[161], 2017 |
| miR-19b-3p (↑) | Human: THP-1 macrophages; Murine: Peritoneal macrophages | Acetylated LDL (AcLDL) | ABCA1 | Mimic inhibits cholesterol efflux to ApoA-I, increasing cholesterol mass | Overexpression of miR-19b decreases reverse cholesterol transport (RCT) in vivo; mimic reduces high density lipoprotein (HDL) levels, increases lesion area and lipid content in apoE-/- mice fed a Western diet (WD); inhibitor achieves the reverse | Lv et al[162], 2014 |
| miR-19b-3p (↓) | Human: THP-1 macrophages; Murine: Peritoneal macrophages | AcLDL + diosgenin | ABCA1 | Inhibitor enhances ABCA1 cholesterol efflux | Inhibitor promotes RCT in vivo, elevates HDL levels, reduces aortic lipid deposition and plaque area in apoE-/- mice (WD) | Lv et al[163], 2015 |
| miR-20a/b (-5p) | Human: THP-1 macrophages; Murine: RAW264.7 macrophages | oxLDL | ABCA1 | Mimic decreases cholesterol efflux to apoA-I, and increases macrophage cholesterol content | Mimic reduces hepatic expression of ABCA1 and high-density lipoprotein (HDL) levels, impairs reverse cholesterol transport and promotes atherogenesis in apoE-/- mice | Liang et al[164], 2017 |
| miR-21-5p | Murine: RAW 264.7 macrophages | OxLDL ± LPS (lipopoly-saccharide) | Toll like receptor 4 (TLR4); NF-κB | LPS stimulation of miR-21 inhibits foam cell formation and reduces secretion of IL-6, IL-12, TNF-α | - | Feng et al[165], 2014 |
| miR-21-5p | Murine: Bone-marrow derived macrophages | AcLDL | Mitogen-activated protein kinase kinase 3 (MKK3) | MiR21-/- macrophages exhibit increased ABCG1 degradation and decreased cholesterol efflux, enhancing foam cell formation. | Most abundant miR in murine macrophages; levels elevated in aortic plaque macrophages isolated from LDL receptor knockout (Ldlr-/-) (WD) mice; knockout of miR-21 enhances arterial macrophage accumulation, production of inflammatory cytokines | Canfrán-Duque et al[166], 2017 |
| miR-23a-5p (↑) miR-23a-3p | Murine: RAW 264.7 macrophages | oxLDL | ABCA1/G1 | Inhibitor enhances cholesterol efflux and decreases foam cell formation via upregulation of ABCA1/G1 expression | Plasma levels correlate with plaque progression and vulnerability in patient with acute ischemic stroke. Long-term systemic delivery of antagomir reduces atheroma and promotes plaque stability (apoE-/- mice) | Yang et al[167], 2018 |
| miR-24-3p | Primary: Human monocyte-derived macrophages | Colony stimulating factor (CSF) | Matrix metallo-proteinase (MMP)-14 | Inhibitor increases macrophage invasive capacity | Hsa-miR-24 levels inversely correlate with MMP-14 protein, and lesion instability Inhibitor increases lesion size and MMP-14 levels in apoE-/- mice (HFD) | Di Gregoli et al[168], 2014 |
| miR-27a/b (-3p) | Human: THP-1 macrophages; Murine: RAW264.7 macrophages | AcLDL | ABCA1 | Mimic decreases cholesterol efflux, and increases free cholesterol content in macrophages, but blocks uptake of oxLDL [Lipoprotein lipase (LPL), cluster of differentiation (CD36)] and inhibits cholesterol esterification | - | Zhang et al[169], 2014 |
| miR-28a-5p (↑) | Murine: RAW264.7 macrophages | oxLDL | LDL receptor class A domain containing 3 (LRAD3) | - | - | Li et al[170], 2018 |
| miR-30c-5p | Human: THP-1 macrophages | oxLDL | Caspase 3 | Cluster differentiation (CD) 36-dependent uptake of oxLDL reduces miR-30c-5p, enhancing IL secretion | Low serum levels of hsa-miR-30c-5p predict carotid atherosclerosis. Antagomir impairs endothelial healing following carotid injury (C57BL/6J mice) | Ceolotto et al[171], 2017 |
| miR-30c-1-3p (↑) | Murine: RAW264.7 macrophages | oxLDL | Oxidized LDL (lectin-like) receptor 1 (LOX-1) | - | - | Li et al[170], 2018 |
| miR-33a/b (-5p) (↑) | Human: THP-1 macrophages | oxLDL ± C. pneumoniae | ABCA1 | Inhibitor promotes cholesterol efflux compared with C. pneumoniae control | - | Zhao et al[172], 2014 |
| miR-33a-5p | Human: THP-1 macrophages | Vaspin ± LPS | ABCA1 | Vaspin decreases expression of miR-33a via inhibition of NF-κB, enhancing cholesterol efflux | - | Gao et al[173], 2018 |
| miR-33 | Human: THP-1 macrophages; Murine: Peritoneal macrophages | - | Peroxisome proliferator activator receptor coactivator 1 (PGC1A), pyruvate dehydrogenase kinase 4 (PDK4), solute carrier family 25 member 25 (SLC25A25), nuclear respiratory factor 1 (NRF1), transcription factor A, mitochondrial (TFAM) | Inhibitor enhances mitochondrial respiration, and cholesterol efflux to apoA-I | Antagomir reduces atheroma in apoE-/- mice (WD) | Karunakaran et al[154], 2015 |
| miR-33 | Murine: Peritoneal macrophages | AcLDL | Autophagy protein 5 (Atg5); autophagy-related 12 (Atg12), microtubule-associated protein light chain 3 (Map11c3b), AMP-activated protein kinase κ1 (Prkaa1), lysosomal associated membrane protein 1 (Lamp1), transcription factor EB (TFEB), Forkhead box O-3 (FOXO3) | Mimic inhibits the breakdown of lipid droplets by repressing effectors of macrophage autophagy. Silencing promotes lipid droplet catabolism, aiding ABCA1-dependent cholesterol efflux | Inhibition restores defective autophagy in aorta and macrophages of Ldlr-/- mice | Ouimet et al[153], 2017 |
| miR-33a-5p (↑) | Human: THP-1 macrophages | oxLDL | ABCA1 | Mimic decreases the expression of ABCA1 and promotes lipid accumulation in macrophages, while the inhibitor achieves the reverse | Levels are elevated in individuals at risk of atherosclerosis | Kim et al[174], 2017 |
| miR-34a-5p (↓) | Human: THP-1 macrophages | oxLDL + Hcy | Histone deacetylase 1 (HDAC1) | Overexpression of miR-34a reduces HDAC1 levels in foam cells, while knockdown achieves the reverse; HDAC1 induces homocysteine (Hcy) dependent foam cell formation | Levels of miR-34a decrease, and expression of HDAC1 increases, in the aorta of apoE-/- mice fed a high methionine diet | Zhao et al[175], 2017 |
| miR-98-5p (↓) | Murine: Peritoneal macrophages | oxLDL | Oxidized LDL (lectin-like) receptor 1 (LOX-1) | Mimic reduces expression of LOX-1 and inhibits foam cell formation; inhibitor achieves the reverse | Mimic decreases expression of LOX-1 and lipid accumulation in the aortic root in apoE-/- mice (HFD); inhibitor achieves the reverse | Dai et al[176], 2018 |
| miR-125b-5p (↑) | Murine: RAW 264.7 macrophages | LPS | NF-κB | Silencing of CD40 downregulates levels of miR-125; LPS stimulates miR-125b expression | miR-125b levels are increased in atherosclerosis; siRNA-CD40 apoE-/- mice exhibit reductions in lesion area | Hueso et al[177], 2016 |
| miR-128- (↓) | Murine: RAW 264.7 macrophages | oxLDL | - | Mimic reverses the pro-atherogenic impact of long non-coding (lnc)RNA NEAT1 on foam cell formation | - | Chen et al[178], 2018 |
| miR-133a | Murine: RAW 264.7 macrophages | oxLDL | Testicular orphan nuclear receptor 4 (TR4) | Mimic prevents TR-4 mediated enhancement of lipid uptake via CD36 | - | Peng et al[179], 2016 |
| miR-134-5p | Human: THP-1 macrophages | oxLDL | Angiopoietin (ANGTPL)/lipoprotein lipase (LPL) | LPL activity and protein, inflammatory cytokines and cholesterol mass enhanced by miR-134 mimic; inverse achieved using an inhibitor | - | Lan et al[180], 2016 |
| miR-134-5p | - | - | ANGTPL4/LPL | - | Mimic increases atherosclerotic lesions, release of proinflammatory cytokines and peritoneal macrophage lipid accumulation in apoE-/-(HFD) mice; inhibitor achieves the reverse | Ye et al[181], 2018 |
| miR-144-3p | Human: THP-1 macrophages;Murine: Peritoneal and J774.1 macrophages | Liver X receptor ligand T0901317 | ABCA1 | Mimic reduces cholesterol efflux to apoA-I in macrophages | Mimic reduces HDL levels in vivo (C57BL/6); inhibitor achieves the reverse | Ramirez et al[182], 2013 |
| miR-144-3p | Human: THP-1 macrophages | oxLDL | ABCA1 | Mimic reduces cholesterol efflux and enhances expression of cytokines (IL-1, TNF-α, IL-6) | Agomir inhibits RCT in vivo, and accelerates atherosclerosis in apoE-/- mice (HFD). Circulating levels of miR-144-3p correlate with acute myocardial infarction | Hu et al[183], 2014 |
| miR-146a-5p | Murine: Peritoneal macrophages (wild type and apoE-/-) | NF-κB | Increases in miR-146a inhibit pro-inflammatory responses in macrophages (TNF-α) | miR-146a mimic inhibits inflammation and plaque development in apoE-/- x Ldlr-/- and Ldlr-/- mice (HFD) | Li et al[184], 2015 | |
| miR-146b-5p (↑) | Human: THP-1 macrophages | oxLDL | TNF receptor (TNFR) associated factor 6 (TRAF6) | Inhibition promotes inflammation and lipid uptake during formation of foam cells | Levels are elevated in foam cells, and clinical specimens from patients with atherosclerosis | Lin et al[185], 2017 |
| miR-148a-5p miR-152-3p | - | - | DNA methyl-transferase 1 (DNMT1) | Viral overexpression reduces expression of DNMT1, increases levels of adipocyte differentiation related protein (ADRP) and enhances cholesterol accumulation in foam cells; down-regulation achieves the reverse | Aortic levels increased in hyperhomo-cysteinaemic apoE-/- mice | Yang et al[186], 2017 |
| miR-150-5p (↑) | Human: THP-1 macrophages | oxLDL | Adiponectin receptor 2 (ADIPOR2) | Mimic inhibits lipid accumulation, increasing cholesterol efflux to apoA-I and HDL; an inhibitor achieves the reverse. Down-regulation of ADIPOR2 replicates the impact of the miR-150 mimic | - | Li et al[187], 2016 |
| miR-155-5p (↑) | Human: Peripheral blood monocytes | oxLDL | - | - | - | Chen et al[178], 2009 |
| miR-155-5p (↑) | Murine: RAW 264.7 macrophages | oxLDL | HMG-box transcription factor 1 (HBP1) | Enhances lipid uptake and reactive oxygen species production by macrophages | Antagomir decreases lipid accumulation in macrophages and lesion formation in apoE-/- mice (HFD). Level is up-regulated in CD14+ monocytes from coronary heart disease (CHD) patients | Tian et al[188], 2014 |
| miR-155-5p (↑) | Human: THP-1 macrophages | oxLDL | Calcium-regulated heat stable protein 1 (CARHPS1)-TNF-α | Mimic blocks lipid uptake and suppresses expression of TNF-α; inhibitor achieves the reverse | Elevated in clinical samples (plaque and plasma) from patients with atherosclerosis | Li et al[189], 2016 |
| miR-155-5p | Human: THP-1 macrophages | - | T-cell immunoglobulin and mucin domain-3 (Tim-3) | Mimic enhances expression of cholesteryl ester (CE) hydrolase (CEH). Overexpression inhibits foam cell formation, intracellular CE accumulation and enhances efflux of cholesterol | - | Zhang et al[190], 2018 |
| miR-181a-5p (↓) | Human: THP-1 macrophages | oxLDL | Mitogen-activated protein kinase kinase 1 (MEK1) | Activates MEK/ERK/NF-κB, upregulates NLR family leucine-rich repeat protein 3 (NRLP3) inflammasome-related proteins (NRLP, caspase-1, IL-18, IL-1) | - | Song et al[191], 2019 |
| miR-181a-5p (↑) | Human: THP-1 macrophages | oxLDL | Toll-like receptor 4 (TLR4) | Decreases expression of CD36 protein, and lipid [Total cholesterol (TC), Triglyceride (TG)] accumulation. Inhibits THP-1 apoptosis, and increases Il-6, IL-1, TNF-α protein expression | - | Du et al[192], 2018 |
| miR-188-3p (↑) | - | - | - | - | Overexpression induces intravascular lipid accumulation, suppresses oxidation and macrophage inflammation in apoE-/- mice, and reduces serum levels of Regulated upon activation normal T-cell expressed and secreted (RANTES), LOX1 and inducible Nitric Oxide Synthase (iNOS) | Zhang et al[193], 2018 |
| miR-212-3p | Human: THP-1 macrophages | oxLDL | Sirtuin 1 (SIRT1) | Overexpression promotes lipid accumulation during foam cell formation, and reduces ABCA1 expression and cholesterol efflux; depletion achieves the reverse | Levels are decreased in atheroma and macrophages in apoE-/- mice (HFD) | Miao et al[194], 2018 |
| miR-216a-5p | Human: THP-1 macrophages | oxLDL | Cystathionine-γ-lyase (CSE) | Mimic inhibits expression of ABCA1, decreases phosphorylation of phosphatidyl-inositol 3-kinase (PI3K) and protein kinase B (AKT), and reduces ABCA1 expression and cholesterol efflux, promoting lipid accumulation; inverse occurs with the inhibitor | - | Gong et al[195], 2016 |
| miR-217 | - | - | - | - | Serum levels are negatively correlated with plaque development in apoE-/- mice (HFD). Mimic reduces intimal media thickness, reduces levels of pro-atherogenic lipoproteins and inhibits inflammation in the same model | Liu et al[196], 2018 |
| miR-221-3p (↓) | Murine: RAW 264.7 macrophages | oxLDL | A disintegrin and metalloprotease-22 (ADAM22) | Mimic reduces foam cell formation and apoptosis; inhibitor achieves the reverse | - | Zhuang et al[197], 2019 |
| miR-223 (↓) | Murine: Bone marrow derived macrophages; Murine: RAW264.7 macrophages | LPS, oxLDL | TLR4 | Overexpression reduces foam cell formation, and production of pro-inflammatory cytokines via repression of NK-κB signaling; inhibitor achieves the reverse | Elevated levels in aortic lesions in apoE-/- mice (HFD) | Wang et al[198], 2015 |
| mir-302a-3p (↓) | Primary: Mouse macrophages | oxLDL, AcLDL | ABCA1 | Mimic decreases cholesterol efflux to apoA-I | Inhibitor enhances ABCA1 in hepatic and aortic tissues of Ldlr-/- mice (HFD), increases HDL and reduces plaque size and inflammation | Meiler et al[199], 2015 |
| miR-361-5p | Human: THP-1 macrophages | oxLDL | LPL | Mir-361-5p is upregulated by apelin, resulting in suppression of LPL translation, inhibition of lipid accumulation and proinflammatory cytokine secretion | - | Zhang et al[200], 2017 |
| miR-378-3p (↑) | Human: THP-1 macrophages; Murine: J774.1 macrophages | oxLDL ± coenzyme Q10 | ABCG1 | Coenzyme Q10 (Q10) protects cholesterol efflux by reducing expression of miR-378 | Q10 promotes RCT and reduces atheroma in apoE-/- mice (HFD) | Wang et al[201], 2014 |
| miR-382-5p (↑) | Human: THP-1 macrophages | oxLDL, AcLDL | Nuclear factor 1A (NFIA) | Mimic increases cholesterol content and reduces cholesterol efflux; enhances LPS-stimulated production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1) | - | Hu et al[108], 2015 |
| miR-486-5p | Human: THP-1 macrophages | oxLDL | Histone acetyl-transferase 1 (HAT1) | Mimic downregulates the expression of ABCA1, limiting cholesterol efflux and promoting foam cell formation; inhibitor achieves the reverse | - | Liu et al[202], 2016 |
| miR-497-5p (↑) | Human: THP-1 macrophages | oxLDL | Apelin | Overexpression of miR-497 promotes cholesterol efflux and decreases cholesterol efflux; inhibitor achieves the reverse | - | Cui et al[203], 2017 |
| miR-758-5p | Human: THP-1 macrophages | oxLDL | CD36 | Mimic decreases uptake of DiI-labelled OxLDL via modulation of CD36; inhibitor achieves the reverse | - | Li et al[204], 2017 |
TargetScan and miRDB were used to confirm mouse miRNA target prediction in humans; where (↑↓) is not indicated, the level of miRNA was not confirmed altered by macrophage lipid accumulation. ABCA1: ATP binding cassette transporter A1; ABCG1: ATP binding cassette transporter G1; oxLDL: Oxidized low density lipoprotein; AcLDL: Acetylated low density lipoprotein; ADAM22: A disintegrin and metalloprotease-22; ADIPOR2: Adiponectin receptor 2); ADRP: Adipocyte differentiation related protein; AKT: Protein kinase B; ANGTPTL4: Angiopoetin-like 4; ApoE: Apolipoprotein E; ATG5: Autophagy protein 5; ATG12: Autophagy-related 12; CARHPS1: Calcium-regulated heat stable protein 1; CD: Cluster of differentiation; CEH: Cholesteryl ester hydrolase 1; CSE: Cystathionine-γ-lyase; CSF: Colony stimulating factors; DNMT1: DNA methyltransferase 1; ERK: extracellular signal-regulated kinase; FOXO3: Forkhead protein O3; HAT1: Histone acetyltransferase 1; HBP-1: HMG-Box transcription factor 1; Hcy: Homocysteine; HDAC1: Histone deacetylase 1; HFD: High fat diet; IL: Interleukin; ISG15: Interferon-stimulated gene 15; IKKα/β: Inhibitor kappa B kinase alpha/beta; iNOS: Inducible nitric oxide synthase; Lamp1: Lysosomal associated membrane protein 1; lncRNA: Long noncoding RNA; LPL: Lipoprotein lipase; LPS: Lipopolysaccharide; LRAD3: Low density lipoprotein receptor class A domain containing 3; Map11c3b: LC3 microtubule-associated protein light chain 3; MEK1: Mitogen activated protein kinase kinase 1; MEKK1: Mitogen-activated protein kinase kinase kinase 1; MKK3: Mitogen activated protein kinase kinase 3; MMP-14: Matrix metalloproteinase-14; NF-κB: Nuclear factor kappa B; NFAM: Transcription factor A, mitochondrial; NFIA: Nuclear factor 1A; NLRP3: NLR-family, leucine-rich repeat protein 3; NRF1: Nuclear respiratory factor 1; OLR1/LOX1: Oxidized low density lipoprotein (lectin-like) receptor 1; PDCD4: Programmed cell death 4; PDK4: Pyruvate dehydrogenase kinase 4; PGC1-γ: Peroxisome proliferator activated receptor-γ coactivator 1; PI3K: Phosphatidylinositol 3-kinase; Prkaa1: AMP-activated protein kinase-α1; RANTES: Regulated upon activation normal T cell expressed and secreted; SIRT1: Sirtuin 1, NAD-dependent protein deacetylase sirtuin 1; SLC25A25: Solute carrier family 25, member 25; SREBF: Sterol regulatory element-binding transcription factor; STK11: Serine/threonine kinase 11; TC: Total cholesterol; TFEB: Transcription factor EB; TG: Triglyceride; TLR4: Toll-like receptor 4; Tim-3: T-cell immunoglobulin and mucin domain-3; TNF-α: Tumour necrosis factor alpha; TR4: Testicular orphan nuclear receptor 4; TRAF6: TNF receptor (TNFR) associated factor 6; Vaspin: Visceral adipose tissue-derived serine protease inhibitor; WD: Western diet.