1000/1000
Hot
Most Recent
Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs.
miRNA | Target | Expression Change in Cardiovascular Diseases (CVD) and Knockout and Model Mice | In Vitro Effect on Lipid Level and Reverse Cholesterol Transport (RCT) | In Vivo Effect on Lipid Level, RCT and Atherosclerosis |
---|---|---|---|---|
miR-9 | ABCA1 | Plasma level of hsa-miR-9-3p decreased in patients with unstable angina (UA) [76]. | MiR-9-5p directly bound to the 3′-UTR of ABCA1 and reduced its mRNA and protein levels in macrophages [77]. | |
miR-10b | ABCA1/ABCG1 | MiR-10b level increased in atherosclerotic plaques in humans [78]. | MiR-10b directly bound to the 3′-UTR of ABCA1/ABCG1 and suppressed their expression and cholesterol efflux from mouse peritoneal macrophages (MPMs) and human THP-1 monocytes [79]. | In ApoE−/− mice, miR-10b suppressed the expression of ABCA1/ABCG1 and RCT from macrophages to feces, thus contributing to the development of atherosclerosis, the growth of plaques and their instability in the late stages [79][80]. |
miR-17 | ABCA1 | An increase in the level of miR-17-5p has been found in leukocytes of patients with atherosclerosis [81], in plasma of patients with UA [82], acute myocardial infarction (AMI) [83], CAD [84][85]. The serum level of miR-17-5p was also associated with the development of ischemic heart disease (IHD) [86] and the severity of CAD [87]. miR-17-3p levels also increased in atherosclerotic plaques in humans [78]. However, a decrease in the circulating miR-17-5p level has been found in patients with CAD [88] and CHD [89]. | MiR-17-5p directly bound to the 3′-UTR of ABCA1 and suppressed its expression in mouse macrophage RAW264.7 [81]. | The level of miR-17-5p increased in the macrophages of ApoE−/− mice on a high-cholesterol diet [81]. |
miR-19b | ABCA1 | MiR-19b levels elevated in human atherosclerotic plaques and rat aortic tissues of the abdominal aortic aneurysm (AAA) model [90][91], in plasma of patients with AMI [92] and in plasma endothelial microparticles (EMPs) of patients with UA [93]. | MiR-19b directly suppressed ABCA1 expression and cholesterol efflux from MPMs and macrophages derived from human THP-1 monocytes [94]. | In ApoE−/− mice, miR-19b suppressed the expression of ABCA1, RCT and the level of HDL in plasma, thus increasing the size of aortic plaques and contributing to the development of atherosclerosis [94][95]. |
miR-20a/b | ABCA1 | Changes in miR-20a expression in atherosclerosis-associated diseases are multidirectional. Thus, the level of miR-20a increased in human aorta with AAA [96] and in plasma of patients with UA as well [76][82]. In contrast, the level of miR-20a decreased in blood cells of patients with AMI [97] and in plasma of patients with CAD [88]. MiR-20b was also low in blood cells of patients with the peripheral arterial disease (PAD) [98]. Expression of miR-20a/b decreased in the liver of ApoE−/− mice on a high fat diet [75]. | MiR-20a/b bound to the 3′-UTR of ABCA1 and suppressed its expression and cholesterol efflux from THP-1- and RAW 264.7-derived foam cells [75]. | In ApoE−/− mice, miR-20a/b reduced ABCA1 expression in the liver, RCT efficiency and HDL synthesis, thus contributing to the development of atherosclerosis [75]. |
miR-23a | ABCA1ABCG1 | Increased values for miR-23a were associated with atherosclerosis-related diseases, i.e., an increased miR-23a level has been detected in the plasma of patients with acute ischemic stroke (AIS) with vulnerable carotid plaques [99], in plasma of patients with UA [76] and in plasma and PBMCs of patients with CAD [100][101][102][103]. miR-23a levels are correlated with plaque development [99], stenosis degree [100] and poor clinical outcomes in CAD [101]. OxLDL upregulated miR-23a expression in macrophages [99]. However, miR-23a level in plasma decreased within 24 h of stroke onset in humans [104]. | MiR-23a suppressed the activity of 3′-UTR of ABCA1 and ABCG1, reduced their expression and cholesterol efflux, that led to foam cell formation [99]. | In ApoE−/− mice, miR-23a suppressed ABCA1 and ABCG1 expression, promoted atherosclerosis and increased plaque vulnerability [99]. |
miR-24 | SCARB1 | The data are contradictory. Fatty acids increased the expression of miR-24 in HepG2 cells. The miR-24 levels significantly increased in the liver of obese mice [105], in the plasma of patients with stable angina pectoris (AP) [106], in PBMCs of patients with CAD [107]. However, miR-24 levels reduced in blood of patients with atherosclerosis [108] and in plasma of patients with familial hypercholesterolemia (FH) [109]. | MiR-24 directly suppressed the expression of SR-BI by binding to the 3′-UTR of mRNA, thus reducing the selective uptake of HDL-CE by HepG2 and THP-1 cells [105][110]. In addition, steroidogenesis reduced in steroidogenic cells [105]. | In ApoE−/− mice, miR-24 reduced the expression of SR-BI and promoted the formation of atherosclerotic plaques [110]. |
miR-26a/b | ABCA1 | The level of miR-26a-1 increased in plasma of patients with AMI [111]. The level of miR-26b increased in plasma of patients with UA [76], while miR-26a/b increased in EMPs of patients with UA [93]. Moreover, the expression of miR-26b was significantly upregulated in atherosclerotic plaques in humans [78]. However, miR-26b decreased in blood cells of patients with peripheral arterial disease (PAD) [98]. | In RAW 264.7, THP-1, HEK293T and HepG2 cells, miR-26 bound to the 3′-UTR of ABCA1 and suppressed its expression [112]. | |
miR-27a/b | ABCA1 | The level of miR-27a increased in PBMCs of patients with CAD [9] and in plasma of patients with UA [76]. The level of miR-27b significantly increased in sclerotic intima samples and in serum of patients with atherosclerosis obliterans [113], in plasma of patients with AAA [114], as well as in PBMCs of the patients with CAD, and expression levels of miR-27b were significantly correlated with the severity of stenosis [100]. The level of miR-27b elevated in the liver of C57BL/6J mice, as well as in ApoE−/− female mice on a high-fat “Western” diet [115]. However, the decreased levels of miR-27b were observed in blood cells of patients with PAD [98] and in plasma of patients with CAD [88], as well as in aneurysm tissues of patients with AAA [114]. A reduced level of miR-27b is associated with heart failure, atherosclerosis, and the severity of PAD symptoms [116]. | MiR-27a/b directly targeted the 3′-UTR of ABCA1, significantly reducing its mRNA and protein levels in foam cells derived from THP-1 and RAW 264.7, as well as in HepG2 cells [117]. MiR-27a/b also reduced cholesterol efflux from THP-1 macrophages to apoA-I through the suppression of ABCA1. A similar effect of miR-27b on ABCA1 mRNA and protein levels and cholesterol efflux existed for Huh7 cells [118]. | Modulation of miR-27b expression in wild-type mice regulated ABCA1 expression in the liver but does not affect lipid levels [118]. |
miR-28 | ABCA11 | The level of miR-28-5p increased in patients with UA [119][120]. | miR-28-5p targeted the signal-regulated kinase 2 (ERK2) and inhibited its expression that led to increase of ABCA1 expression in THP-1 derived macrophages and HepG2 cells [119][120]. | |
miR-30e | ABCA1 | The expression of miR-30e was significantly upregulated in the serum exosome of patients with CAD [3], in atherosclerotic plaques in humans [78], in plasma of patients with UA [76], and in blood cells of patients with AMI [97]. Moreover, miR-30e is considered as a differential biomarker for AMI [121]. However, there is evidence that miR-30e expression reduced in PBMCs of patients with lower extremities arterial disease (LEAD) [122] and in the whole blood of CAD patients [123]. | MiR-30e directly targeted 3′-UTR of ABCA1 and suppressed its protein expression [3]. | |
miR-34a | ABCA1/ABCG1 | All studies evidence the increase of miR-34a in atherosclerosis- associated diseases. Thus, the level of miR-34a significantly increased in atherosclerotic plaques in humans and in ApoE−/− mice [124][125], in PBMCs of patients with LEAD [122], in plasma of patients with CAD [103][126] and AP [106]. Upregulated miR-34a is considered as a universal marker for AMI and UA [121]. | In HepG2 cells, miR-34a directly interacted with the 3′-UTR of ABCA1 and ABCG1 mRNA and suppressed their expression [124]. Moreover, miR-34a inhibited cholesterol efflux from THP-1 and MPMs cells. | In mice, the downregulation of ABCA1 and ABCG1 by miR-34a promoted RCT suppression to plasma, liver and feces [124]. In ApoE−/− and Ldlr−/− mice, miR-34a promoted dyslipidemia, plaque growth, and instability. |
miR-92a | ABCA1 | The data on miR-92a expression in atherosclerosis are contradictory. The increased level of miR-92a was found in plasma and plasma exosomes of patients with the initial stage of atherosclerosis [127], with CAD [3][128], in aneurysm tissues of AAA [96], in human coronary atherosclerotic plaques [91], in plasma of patients with hypertension, especially with thickening of the carotid artery wall [129], in plasma of patients with UA [82], and with asymptomatic carotid artery stenosis, where it was correlated with the degree of stenosis [130], in PBMCs of CAD patients and in EMPs of patients with UA [93]. Moreover, upregulated miR-92a is considered as a differential biomarker for UA [121]. However, miR-92a expression decreased in the blood of patients with CAD [85][88][131], CHD [89] and atherosclerosis [132], in plasma and atherosclerotic plaques in PAD patients with cardiovascular events (CVEs) [133]. | miR-92a directly targeted 3′-UTR of ABCA1 and suppressed its protein expression [3]. | Increased expression of miR-92a contributed to the development of atherosclerotic plaques under the influence of oxLDL in Ldlr−/− mice [134]. |
miR-93 | ABCA1 | Mostly, miR-93 levels increased in atherosclerosis. Thus, increased miR-93-5p level was detected in plasma of patients with critical coronary stenosis [135], with UA [82], CAD [136] and in blood cells of patients with AMI [97]. Moreover, miR-93 is considered as a universal biomarker for both AMI and UA [121]. However, miR-93 level decreased in CAD patients [137]. | miR-93 directly targeted 3′-UTR of ABCA1 and suppressed its protein expression [137]. | |
miR-96 | SCARB1 | MiR-96 level decreased in ApoE−/− mice on a high-fat diet [138]. The level of miR-96 was significantly upregulated in THP-1 cells stimulated to differentiate into macrophages. | miR-96 directly targeted 3′-UTR of SCARB1, suppressed its protein expression and HDL-C uptake by HepG2 and other human liver cells [138]. However, miR-96 increased HDL-C uptake by THP-1 cells, probably through the regulation of other pathways of cholesterol delivery. | |
miR-101 | ABCA1 | IL-6 and TNF-α induced miR-101 expression in HepG2 cells and THP-1 macrophages [139]. During inflammation, miR-101 may promote the intracellular accumulation of lipids, which results in atherosclerosis. | MiR-101 directly interacted with the 3′-UTR of ABCA1 and suppressed its protein expression, that reduced cholesterol efflux from cells to apoA-I [139]. | |
miR-106b | ABCA1 | Level of miR-106b significantly decreased in plasma of patients with CAD and was correlated with HDL level [85]. MiR-106b level increased in plasma microparticles (MPs) of UA patients [82]. | MiR-106b directly bound to the 3′-UTR of ABCA1 and repressed its translation [140]. In neuronal cells (Neuro2a), miR-106b reduced ABCA1 levels and cholesterol efflux. | |
miR-125a | SCARB1 | miR-125a level decreased in the coronary arteries of patients with atherosclerotic plaques [141] and in the serum of patients with atherosclerosis [142] but increased in atherosclerotic plaques [78]. | MiR-125a directly targeted 3′-UTR of SCARB1 and suppressed SR-BI expression [143]. In rat/mouse Leydig tumor cells, suppression of SR-BI expression at mRNA and protein levels under the influence of miR-125a led to a decrease of HDL-CE uptake by cells and a decrease in HDL-dependent progesterone production. In mouse Hepa1-6 cells, miR-125a also suppressed SR-BI expression and HDL-CE uptake. However, in HepG2 cells, such effect of miR-125a was not found [138]. | |
miR-128 | ABCA1/ABCG1 | In mice on a high-fat diet, the level of miR-128 decreased in the liver, brain, and kidneys [144] but increased in the blood, brain, and heart [145]. miR-128-2 may prevent cholesterol efflux from cells at low cholesterol [144]. | MiR-128-2 targeted 3′-UTR of ABCA1 and ABCG1 and inhibited their expression that led to the suppression of cholesterol efflux from HepG2, MCF7, and HEK293T cells [144]. Similar effects for miR-128-1 were found in mouse macrophages [146]. | miR-128 is inversely correlated with ABCA1 and ABCG1 expression levels in different tissues of mice on a high-fat diet [144]. |
miR-130b | ABCA1 | MiR-130b directly interacted with the 3′-UTR of ABCA1 and suppressed its expression in HepG2 and in mouse macrophages, that led to reducing the cholesterol efflux [146]. | ||
miR-143 | ABCA1 | MiR-143 was up-regulated and ABCA1 was down-regulated in PAH patients [147]. MiR-143 level increased in human coronary atherosclerotic plaques [91]. | MiR-143 directly suppressed the expression of ABCA1 in pulmonary artery smooth muscle cells (PASMCs) [147]. | MiR-143 promoted the development of hypoxia-induced pulmonary arterial hypertension (PAH) in vivo, presumably due to its influence on ABCA1 expression [147]. The studies with Ldlr−/− and Ldlr−/− miR-143/145−/− double knockout mice revealed the contribution of these miRNAs to the development of atherosclerosis [148]. |
miR-144 | ABCA1 | MiR-144 increased in the plasma of patients with UA [76] and CAD [126][149][150], in monocytes of patients with hypertension [151]. However, miR-144 level was decreased in AAA tissue [114]. The level of miR-144 was associated with AMI [152]. LXR ligands increased the expression of miR-144 in mouse and human liver cells and macrophages, that may be important in homeostasis [153]. FXR transactivated miR-144 which suppressed ABCA1 and cholesterol efflux [154]. | MiR-144 directly interacted with the 3′-UTR of ABCA1 and decreased its expression and cholesterol efflux to apoA-I [152][153][155]. | miR-144 reduced the levels of ABCA1 and HDL in the liver and plasma of mice [153][154]. In ApoE−/− mice, miR-144-3p decreased plasma HDL levels, impaired RCT and promoted the development of atherosclerosis [152]. A high-fat diet induced the development of atherosclerosis in miR-144−/− mice [156]. miR-144 promoted lipid accumulation and lipid disorder in F1-zebrafish [157]. |
miR-145 | ABCA1 | Data are contradictory. The level of miR-145 increased in the blood of patients with PAH [147], in plasma of patients with AMI [83] and within 24 h of stroke onset [104]. Upregulated level of miR-145 is considered as a biomarker for both AMI and UA [121]. The miR-145 levels are correlated with the size of the infarction area and may predict a long-term clinical outcome after AMI [158]. However, level of miR-145 decreased in the plasma of patients with AMI [159] and in the plasma and blood of patients with CAD, including very early onset [160], where it is correlated with disease severity [88][123][161]. | MiR-145 targeted 3′-UTR of ABCA1 and suppressed its protein expression and cholesterol efflux from HepG2 cells [155]. | MiR-145 promoted a decrease in the ABCA1 protein in the mouse pancreas, as well as an increase in total cholesterol levels and a decrease in insulin secretion [155]. The studies in Ldlr−/− and Ldlr−/− miR-143/145−/− double knockout mice showed the contribution of these miRNAs to the development of atherosclerosis [148]. |
miR-148 | ABCA1 | The expression of miR-148b reduced in the serum of patients with atherosclerosis and in human aortic smooth muscle cells stimulated by ox-LDL [162]. The level of miR-148-3p increased in the liver of rhesus monkeys on a high-fat diet, as well as in mice (ob/ob) with genetically determined obesity [163]. | MiR-148 directly bound the 3′-UTR of ABCA1 and suppressed its expression [146][155][163]. As a result, miR-148 suppressed cholesterol efflux from HepG2 and mouse macrophages [146]. | In C57BL/6J and ApoE−/− mice on a high-fat diet, miR-148 reduced liver ABCA1 and blood HDL [146]. In Ldlr−/− mice on a high-fat diet, miR-148 contributed to a decrease of ABCA1 in the liver and HDL in blood [163]. |
miR-183 | ABCA1 | In macrophages derived from THP-1, IL-18 promoted an increase in miR-183 expression with a concomitant decrease in ABCA1 expression and cholesterol efflux, which may contribute to the development of atherosclerosis [164]. | MiR-183 directly interacted with the 3′-UTR of ABCA1 and suppressed its expression [164]. | |
miR-185 | SCARB1 | MiR-185-3p was upregulated in atherosclerotic mouse aorta [165]. miR-185 also increased in atherosclerotic plaques in humans [78]. However, in the liver of ApoE−/− mice on a high-fat diet, the miR-185 level decreased [138]. | MiR-185 directly interacted with the 3′-UTR of SCARB1 and suppressed the expression of SR-BI and HDL-C uptake in THP-1 cells and human hepatic cell lines [138]. | |
miR-188 | ABCA1 | MiR-188-3p decreased in ApoE−/− mice with atherosclerosis [166]. | In ApoE−/− mice with atherosclerosis, miR-188-3p upregulated ABCA1 level in serum and promoted a decrease of lipid accumulation within the vessels and atherosclerosis [166]. | |
miR-212 | ABCA11 | The miR-212 level decreased in plaques and macrophages of ApoE−/− mice on a high-fat diet [167]. | In THP-1 macrophages, miR-212 targeted SIRT1, which led to inhibition of ABCA1 expression, decreased cholesterol efflux and increased intracellular lipid accumulation [167]. | |
miR-223 | SCARB1/ABCA11 | miR-223 increased in CVD i.e., in ApoE−/− mice [168], in serum, in the vascular wall of patients with atherosclerosis obliterans [169], in the plasma of patients with AMI [92], PAD with cardiovascular events (CVEs) [133], unstable coronary artery disease (UCAD) [170], coronary artery calcification (CAC) [171] and UA [76][82], in platelets of patients with CAD [172], in atherosclerotic plaques of patients with PAD with cardiovascular events (CVEs) [133], and in aneurysm tissues of patients with AAA [96]. HDL-transported miR-223 elevated in patients with hypercholesterolemia and in Ldlr−/− and ApoE−/− mice on a high-fat diet. miR-223 increased in human hepatocytes with a high level of extracellular cholesterol [173]. An increased miR-223 level is associated with an increased risk of CVD [173]. MiR-223 expression is associated with atherogenesis in CAD [174]. However, the expression of miR-223 decreased in PBMCs of patients with CAD with the lowest stenosis less than 50% [175]. A reduced level of miR-223 is associated with heart failure, atherosclerosis, and the severity of PAD symptoms [116]. In THP-1 macrophages, miR-223 expression was significantly upregulated bur had no effect on SCARB1 and HDL-C uptake [138]. A reduced cholesterol level caused a decrease in the level of miR-223 in J774 macrophages and Huh7 cells [176]. | MiR-223 directly targeted the 3′-UTR of SCARB1, suppressed SR-B1 expression and the uptake of HDL-C in human hepatic cells [138][176]. miR-223 targeted Sp3, the repressor of Sp1-directed ABCA1 transcription. Thus, miR-223 promoted the indirect increase of mRNA and protein levels of ABCA1, as well as the cholesterol efflux to apoA-I in Huh7 cells [176]. | In miR-223−/− mice the level of SR-BI in the liver reduced, but total cholesterol and HDL-C increased in plasma. Cholesterol level increased in the liver of these mice [176]. |
miR-301b | ABCA1 | MiR-301b directly bound to the 3′-UTR of ABCA1 and suppressed its expression in HepG2 and mouse macrophages, that led to a decrease of cholesterol efflux [146]. | ||
miR-302a | ABCA1 | Ox-LDL downregulated miR-302a expression in mouse macrophages [177]. In the liver of Ldlr−/− mice on Western-type diet, miR-302a decreased [178]. | MiR-302a targeted 3′-UTR of ABCA1 and suppressed its protein expression in primary mouse and human macrophages, leading to suppression of cholesterol efflux [177]. | In Ldlr−/− mice on an atherogenic diet, miR-302a suppressed ABCA1 expression in the liver and aorta with a decrease of plasma HDL level, that promoted the growth of plaques, their instability and inflammation [177]. |
miR-361-5p | ABCA1 | MiR-361-5p directly bound to the 3′-UTR of ABCA1 and suppressed its expression [179]. | ||
miR-378 | ABCG1 | MiR-378 levels increased in aortas during the progression of atherosclerosis in ApoE−/−mice [180]. Plasma miR-378 expression was significantly downregulated in patients with CAD [123][181], CHD [89]. Moreover, it is considered as biomarker for risk and severity of CHD [89]. | MiR-378 directly interacted with the 3′-UTR of ABCG1 and suppressed its expression that led to downregulation of cholesterol efflux from mouse and human macrophages [180]. | In ApoE−/− mice, miR-378 presumably downregulated ABCG1 expression in peritoneal macrophages, leading to decreased RCT and atherosclerosis progression [180]. |
miR-486 | ABCA11 | The level of miR-486 increased in the plasma of obese children and is associated with body mass index and other indicators of obesity [182]. The level of miR-486 elevated in the blood of patients with CAD [128] and is associated with the risk of developing cardiovascular diseases [86][183]. | MiR-486 directly bound to 3′-UTR of histone acetyltransferase-1 (HAT1) and suppressed its expression with a concomitant decrease in ABCA1 expression at both mRNA and protein level, that led to cholesterol accumulation in THP-1 cells [184]. | |
miR-613 | ABCA1 | PPAR-γ, which induces the expression of a cascade of genes involved in cholesterol efflux from macrophages, negatively regulated the expression of miR-613 at transcriptional level [185]. | miR-613 targeted 3′-UTR of ABCA1 and suppressed its protein expression, which led to inhibition of cholesterol efflux from THP-1 cells activated by PPAR-γ [185]. | |
miR-758 | ABCA1 | The level of miR-758 decreased in cholesterol-enriched macrophages, as well as in pancreatic macrophages and liver cells in mice on a high-fat diet [186]. The level of miR-758 increased in plaques from patients with hypercholesterolemia compared to plaques of patients with normal cholesterol [187]. | MiR-758 directly interacted with 3′-UTR of ABCA1, suppressed its expression and cholesterol efflux to apoA-I in mouse and human macrophages [186] and HepG2 cells [188]. |