Background: The significance of cholesterol efflux as a predictor of coronary artery disease (CAD) remains controversial. The intracellular cholesterol export via the ABCA1 transporter involves the acceptance of cholesterol by both lipid-free apolipoprotein A-I and high-density lipoproteins (HDL). An estimate of the efficiencies of two reactions is thus required. Methods: HDL from the plasma of 63 control and 76 male CAD patients was obtained by the precipitation of apoB-containing lipoproteins and denatured by urea. We measured apoA-I dissociation concomitant with HDL denaturation by agarose gel electrophoresis followed by immunodetection and the expression of 65 preselected genes in blood mononuclear cells by real-time PCR. The total cholesterol efflux capacity (CEC) of ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from RAW 264.7 macrophages, when preβ-HDL and α-HDL act as competitive inhibitors of each other for the binding to ABCA1 transporter, was measured with intact HDL and pre-denatured HDL as a source of lipid-free apoA-I. Results: The phospholipid:apoA-I and cholesterol:apoA-I ratios in HDL from CAD patients were higher than those for control patients across the full range of plasma HDL-cholesterol levels. ApoA-I partitioned 1.5-fold higher into the water phase for HDL from CAD patients relative to controls. In CAD patients, the dissociation parameter D was inversely correlated with absolute and normalized per apoA-I phospholipid and cholesterol levels in HDL. For control patients, the D parameter was positively correlated with ABCA1 gene expression. For CAD patients, the D parameter was positively correlated with PLTP and inversely with CUBN and ALB gene expression. ApoA-I functionality in ABCA1-mediated cholesterol efflux from RAW 264.7 macrophages to lipid-free apoA-I generated from urea-induced HDL denaturation was similar for HDL from control and CAD groups. The retained CEC of lipid-free apoA-I in CAD may be masked by competition with α-HDL, which has a lower CEC, for ABCA1 binding to preβ-HDL. Conclusions: The enrichment of HDL with cholesterol and phospholipids may contribute to the increased apoA-I dissociation from HDL in CAD. Estimates of both lipid-free apoA-I and intact HDL may be a prerequisites for a detailed study of ABCA1-mediated cholesterol efflux, which could allow these apoA-I forms to be identified as CAD predictors.

The goal of this study was examination of the association between the expression levels of the genes involved in high-density lipoprotein metabolism and atherogenesis and underlying metabolic pathways and the number of stenotic coronary arteries. Expression of 65 preselected genes in the peripheral blood mononuclear cells of the control patients (n = 63) and patients with coronary artery disease (CAD) with one or two (low stenosis group, n = 35) or three or four (high stenosis group, n = 41) stenotic vessels, confirmed by coronary angiography, was measured with real-time PCR. Functional enrichment analysis was applied for annotation of differentially expressed genes. Protein products of the differentially expressed genes (DEGs) in the CAD patients compared to the controls were associated with metabolic pathways related to assembly, remodeling, and clearance of plasma lipoproteins, as well as with signaling and regulation of expression of the genes involved in cholesterol transport and efflux. However, comparison of the gene expression profiles and associated metabolic pathways between the groups with high versus low stenosis revealed specific differences between these groups. Expression of the CETP, PLTP, CD36, IL18, ITGB3, S100A8, S100A12, and VEGFA genes increased with the increase of the number of stenotic vessels, which suggests involvement of these genes in stenosis expansion via lipoprotein metabolism, inflammation, angiogenesis, and innate immunity. The set of genes ITGB3, VEGFA, and CETP was selected as a new gene expression signature of expansion of the coronary artery stenosis, which was validated with the GSE12288 dataset from the Gene Expression Omnibus database, demonstrating an average odds ratio (OR) of 7.49 (95

The significance of cholesterol efflux as a predictor of coronary artery disease (CAD) remains controversial. The major pathway of the export of intracellular cholesterol by the ABCA1 transporter includes the acceptance of effluxed cholesterol by lipid-free apolipoprotein A-I and/or high-density lipoproteins (HDL). To separate the contribution of lipid-free and lipid-bound apoA-I with different efficiencies in the total cholesterol efflux and underlying mechanism, we measured apoA-I dissociation concomitant with HDL denaturation, the expression of preselected genes, and the efficiency of cholesterol efflux. HDL preparations from plasma of 63 control and 76 CAD male patients were denatured by 4.25 M urea at the transition midpoint. ApoA-I partitioned 1.5-fold higher into the water phase for HDL from CAD patients relative to controls. The dissociation parameter D was reciprocally correlated with phospholipid and cholesterol levels and PL:apoA-I ratio in HDL from CAD patients. For control patients, the D parameter was positively correlated with CETP and ABCA1 expression level. For CAD patients, the D parameter was negatively correlated with CUBN and ALB expression levels that may be associated with the increased catabolism of lipid-free apoA-I. The apoA-I functionality in ABCA1-mediated cholesterol efflux from RAW 264.7 macrophages to urea-pretreated HDL revealed by Vm, Km, and Vm/Km values was similar for HDL from both cohorts. The enrichment of HDL with phospholipid and cholesterol could be involved in the increased apolipoprotein dissociation in CAD. The estimates of the contribution of both lipid-free and lipid-bound apoA-I to total cholesterol efflux are required to accurately describe them as CAD predictors. ### Competing Interest Statement The authors have declared no competing interest.

Background: The associations of high-density lipoprotein (HDL) level and functionality with lipid metabolism, inflammation, and innate immunity in coronary artery disease (CAD) remain controversial. The differential expression of a set of genes related to HDL metabolism (24 genes) and atherogenesis (41 genes) in peripheral blood mononuclear cells (PBMC) from CAD and control patients with varied HDL cholesterol (HDL-C) levels was compared. Methods: 76 male patients 40–60 years old with CAD diagnosed by angiography and 63 control patients were divided into three groups with low, normal (1.0–1.4 mM), and increased HDL-C levels. Transcript levels were measured by real-time PCR. The differentially expressed genes (DEGs) and associated metabolic pathways were analyzed for three groups, with prevalent CAD as an outcome. Results: The common feature was the increased odds ratio values for liver X receptor (LXR) gene expression for three patient groups. CAD patients with low HDL-C possessed 24 DEGs with lower expression of genes involved in cholesterol efflux, and down-regulated SREBF1 and ABCG1 are suggested as gene signatures. CAD patients with normal HDL-C possessed nine DEGs with down-regulated ITGAM and ALB as gene signatures. CAD patients with increased HDL-C possessed 19 DEGs with down-regulated APOA1 and HMGCR as gene signatures. With gene expression signatures, one standard deviation higher average gene expressions were associated with 5.1-, 48.8-, and 38.9-fold fewer CAD cases for three patient groups. As HDL-C increased in CAD patients, the expression of ABCG1, CUBN, and HDLBP genes increased, while the expression of HMGCR and NPC2 genes, involved in cholesterol synthesis and trafficking, decreased. The expression of CD14, CD36, S100A8, S100A9, S100A12, TLR5, TLR8, and VEGFA genes, involved in angiogenesis and inflammation mainly via nuclear factor-κB (NF-κB), decreased. Conclusions: The increased accumulation of cholesteryl ester in PBMC from patients with low HDL-C was suggested. This assumption contrasts with the suggested accumulation of free cholesterol in PBMC from patients with increased HDL-C, concomitant with suppression of cholesterol synthesis and traffic to the plasma membrane, and with an inflammatory state controlled by depressed CD36-mediated and upregulated apoE-mediated immunometabolic signaling. Gene signatures may be used for the diagnosis, prognosis, and treatment of CAD in dependence on HDL-C levels.

Differential expression of genes (DEGs) in coronary artery disease (CAD) and the association between transcript level and high-density lipoprotein cholesterol (HDL-C) were studied with 76 male patients with CAD and 63 control patients. The transcript level of genes related to HDL metabolism (24 genes) and atherosclerosis-prone (41 genes) in RNA isolated from peripheral blood mononuclear cells was measured by real-time RT-PCR. Twenty-eight DEGs were identified. The expression of cholesterol transporters, ALB, APOA1, and LCAT was down-regulated, while the expression of AMN, APOE, LDLR, LPL, PLTP, PRKACA, and CETP was up-regulated. The systemic inflammation in CAD is evidenced by the up-regulation of IL1B, TLR8, CXCL5, and TNFRSF1A. For the controls, TLR8 and SOAT1 were negative predictors of the HDL-C level. For CAD patients, PRKACG, PRKCQ, and SREBF1 were positive predictors, while PRKACB, LCAT, and S100A8 were negative predictors. For CAD patients, the efficiency of reverse cholesterol transport is 73-79%, and intracellular free cholesterol seems to accumulate at hyperalphalipoproteinemia. Both atheroprotective (via S100A8) and proatherogenic (via SREBF1, LCAT, PRKACG, PRKACB, and PRKCQ) associations of gene expression with HDL-C determine HDL functionality in CAD patients. The selected key genes and involved pathways may represent HDL-specific targets for the diagnosis and treatment of CAD and atherosclerosis.

Over the past decade, numerous studies have shown that circular RNAs (circRNAs) play a significant role in coronary artery atherogenesis and other cardiovascular diseases. They belong to the class of non-coding RNAs and arise as a result of non-canonical splicing of premature RNA, which results in the formation of closed single-stranded circRNA molecules that lack 5′-end caps and 3′-end poly(A) tails. circRNAs have broad post-transcriptional regulatory activity. Acting as a sponge for miRNAs, circRNAs compete with mRNAs for binding to miRNAs, acting as competing endogenous RNAs. Numerous circRNAs are involved in the circRNA–miRNA–mRNA regulatory axes associated with the pathogenesis of cardiomyopathy, chronic heart failure, hypertension, atherosclerosis, and coronary artery disease. Recent studies have shown that сirc_0001445, circ_0000345, circ_0093887, сircSmoc1-2, and circ_0003423 are involved in the pathogenesis of coronary artery disease (CAD) with an atheroprotective effect, while circ_0002984, circ_0029589, circ_0124644, circ_0091822, and circ_0050486 possess a proatherogenic effect. With their high resistance to endonucleases, circRNAs are promising diagnostic biomarkers and therapeutic targets. This review aims to provide updated information on the involvement of atherogenesis-related circRNAs in the pathogenesis of CAD. We also discuss the main modern approaches to detecting and studying circRNA–miRNA–mRNA interactions, as well as the prospects for using circRNAs as biomarkers and therapeutic targets for the treatment of cardiovascular diseases.

Background and Aims: To reveal the predictors of plasma HDL-cholesterol variability in CAD patients at transcriptome subset level. Methods: 77 male patients 40-60 years old with CAD diagnosed by angiography were enrolled in the study. Two sets of genes related to HDL metabolism (HDL-cluster with 23 genes) and atherosclerosis-prone (atherogen-cluster with 41 genes) were selected. Transcript levels in RNA isolated from peripheral blood mononuclear cells (PBMC) were measured by real-time RT-PCR. Results: For HDL-cluster by bivariate correlation, HDL-C was positively associated with ABCG1, ALB, CUBN, HDLBP, PRKACG transcripts. However, HDL-C was negatively associated with BMP1, LCAT, PRKACB transcripts. Importantly, HDL-C was negatively associated with HMGCR transcript. For atherogen-cluster, HDL-C was positively associated with IL18RAP, PRKCQ, and SREBF1 transcripts, while negatively with the following fourteen transcripts: CD14, CD36, CYBA, F5, MGST1, NPC2, OLR1, S100A12, S100A8, S100A9, SLP1, TLR5, TLR8, and VEGFA. The contribution of gene transcripts into variability of HDL-C was explored also with multiple linear regression. Only transcripts from both gene clusters with significant correlations with HDL-C were included as independent variables, together with plasma TG and non-HDL-C. IL18RAP and SREBF1 transcripts were positive predictors, while BMP1 and LCAT transcripts were negative predictors of HDL-C variability, totally explaining 81% variation of HDL-C. Conclusions: The decrease of BMP1 activity that cleaves proA-I to the mature apoA-I active in cholesterol efflux, with the decrease of large HDL due to low LCAT activity, may underlie the negative association of BMP1 and LCAT transcripts with HDL-C level. SREBP1-IL18RAP axis seems to link intracellular lipid metabolism to the innate immune response.

Cholesterol efflux is the first and rate-limiting step of reverse cholesterol transport (RCT) from peripheric cells to the liver. The involvement of high-density lipoprotein (HDL) in RCT determines the atheroprotective properties of HDL. Cholesterol efflux from different membrane pools includes both passive and energy-dependent processes. The first type of route consists of cholesterol desorption from the cell membrane into the unstirred layer adjacent to the cell surface and diffusion in the water phase. Moreover, the selective uptake and facilitated diffusion of cholesterol and cholesteryl ester molecules through the hydrophobic tunnel in the scavenger receptor BI molecule does not require energy consumption. The second type of route includes active cholesterol export by the ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Several cholesterol acceptors specifically bind cholesterol and phospholipid molecules, and cholesterol binding to the albumin molecule, which acts as a shuttle, significantly increases cholesterol movement between acceptors and red blood cells, thus functioning as a sink for cholesterol. Cholesterol and phospholipid molecules effluxed from macrophages by ABCA1 are accepted exclusively by the lipid-free apolipoprotein apoA-I, which is the major protein moiety of HDL, whereas those effluxed by ABCG1 are accepted by HDL. ABCA1- and ABCG1-mediated cholesterol transport, together with cholesterol diffusion, largely determine cholesterol turnover at the physiological level of intracellular cholesterol. However, at cholesterol overload, ABCA1-mediated efflux prevails over other routes. The exchange of apoA-I between lipid-free and lipid-associated states and the synergism of nascent and mature HDL contribute to cholesterol efflux efficiency. Moreover, extracellular cholesterol deposits and microvesicles may be involved in RCT.

Background and Aims : The relation between apoA-I dissociation and HDL concentration that may determine the atheroprotective properties of HDL remains unknown.Methods: HDL was prepared from plasma samples of 48 middle-aged male patients without coronary atherosclerosis by precipitation of apoB-containing lipoproteins by polyethylene glycol. Urea-induced HDL denaturation and concomitant apoA-I dissociation were followed by the increase of apoA-I-containing prebeta-fraction in immunoreplica after HDL electrophoresis in agarose gel and by the increase of ABCA1-mediated efflux of fluorescent analogue BODIPY-Cholesterol from RAW 264.7 macrophages.Results: Urea-induced apoA-I dissociation from HDL surface occurs as a cooperative transition from lipid-bound to fully dissociated apolipoprotein. The resistance of HDL structure to denaturation was compared by the D parameter that corresponds to the degree of apoA-I dissociation after the incubation of HDL preparations at the same dilution for 6 hrs at 25°С at pH 7.4 in 4.25 M urea as a half-transition region. The D parameter negatively correlated with choline-containing phospholipid level in HDL preparations (r = -0.603, p = 5.8·10-6). Dissociated apoA-I determines the increase of ABCA1-mediated efflux of BODIPY-Cholesterol from RAW 264.7 macrophages to patient HDL.Conclusions: The stability of apolipoprotein-lipid interactions depends on the level of HDL phospholipids at apoA-I distribution between lipid and water phases. The fraction of extracellular lipid-free apoA-I may increase in atheroma with local acidosis and low HDL level as a compensatory trigger of ABCA1-dependent cholesterol efflux from macrophage. The ability of HDL to donate lipid-free apoA-I as a primary cholesterol acceptor may represent a new functional property of HDL. Background and Aims : The relation between apoA-I dissociation and HDL concentration that may determine the atheroprotective properties of HDL remains unknown. Methods: HDL was prepared from plasma samples of 48 middle-aged male patients without coronary atherosclerosis by precipitation of apoB-containing lipoproteins by polyethylene glycol. Urea-induced HDL denaturation and concomitant apoA-I dissociation were followed by the increase of apoA-I-containing prebeta-fraction in immunoreplica after HDL electrophoresis in agarose gel and by the increase of ABCA1-mediated efflux of fluorescent analogue BODIPY-Cholesterol from RAW 264.7 macrophages. Results: Urea-induced apoA-I dissociation from HDL surface occurs as a cooperative transition from lipid-bound to fully dissociated apolipoprotein. The resistance of HDL structure to denaturation was compared by the D parameter that corresponds to the degree of apoA-I dissociation after the incubation of HDL preparations at the same dilution for 6 hrs at 25°С at pH 7.4 in 4.25 M urea as a half-transition region. The D parameter negatively correlated with choline-containing phospholipid level in HDL preparations (r = -0.603, p = 5.8·10-6). Dissociated apoA-I determines the increase of ABCA1-mediated efflux of BODIPY-Cholesterol from RAW 264.7 macrophages to patient HDL. Conclusions: The stability of apolipoprotein-lipid interactions depends on the level of HDL phospholipids at apoA-I distribution between lipid and water phases. The fraction of extracellular lipid-free apoA-I may increase in atheroma with local acidosis and low HDL level as a compensatory trigger of ABCA1-dependent cholesterol efflux from macrophage. The ability of HDL to donate lipid-free apoA-I as a primary cholesterol acceptor may represent a new functional property of HDL.

Background and Aims : To model the interaction of lipid-free apoA-I with cholesterol molecules that exist in various self-associated forms in extracellular space. Cholesterol dimerization is exploited to reconcile the existing experimental data on cholesterol binding to apoA-I with extremely low critical micelle concentration of cholesterol.Methods: The interaction of differently self-associated lipid-free apoA-I with cholesterol monomer and tail-to-tail (TT) or face-to-face (FF) cholesterol dimer was modelled with Schrödinger package. Two crystal structures of 1-43 N-truncated apolipoprotein Δ(1-43)A-I tetramer (PDB ID: 1AV1, structure B), 185-243 C-truncated apolipoprotein Δ(185-243)A-I dimer (PDB ID: 3R2P, structure M) were exploited.Results: Cholesterol monomers bind to multiple binding sites in apoA-I monomer, dimer and tetramer with low, moderate and high energy, still insufficient to overcome the thermodynamic restriction by cholesterol micellization (-52.8 kJ/mol). However, apoA-I monomer and dimer existing in structure B, that contain nonoverlapping and non-interacting pairs of binding sites with high affinity for TT and FF cholesterol dimers, can bind in common 14 cholesterol molecules that correspond to existing values. ApoA-I monomer and dimer in structure M can bind in common 6 cholesterol molecules. The values of respective total energy of cholesterol binding for both B and M structures exceed the free energy of cholesterol micellization.Conclusions: Cholesterol dimers may simultaneously interact with extracellular monomer and dimer of lipid-free apoA-I, that accumulate at acid pH in atheroma. The thermodynamically allowed apolipoprotein-cholesterol interaction outside the macrophage may represent a new mechanism of cholesterol transport by apoA-I from atheroma, in addition to ABCA1-mediated cholesterol efflux. Background and Aims : To model the interaction of lipid-free apoA-I with cholesterol molecules that exist in various self-associated forms in extracellular space. Cholesterol dimerization is exploited to reconcile the existing experimental data on cholesterol binding to apoA-I with extremely low critical micelle concentration of cholesterol. Methods: The interaction of differently self-associated lipid-free apoA-I with cholesterol monomer and tail-to-tail (TT) or face-to-face (FF) cholesterol dimer was modelled with Schrödinger package. Two crystal structures of 1-43 N-truncated apolipoprotein Δ(1-43)A-I tetramer (PDB ID: 1AV1, structure B), 185-243 C-truncated apolipoprotein Δ(185-243)A-I dimer (PDB ID: 3R2P, structure M) were exploited. Results: Cholesterol monomers bind to multiple binding sites in apoA-I monomer, dimer and tetramer with low, moderate and high energy, still insufficient to overcome the thermodynamic restriction by cholesterol micellization (-52.8 kJ/mol). However, apoA-I monomer and dimer existing in structure B, that contain nonoverlapping and non-interacting pairs of binding sites with high affinity for TT and FF cholesterol dimers, can bind in common 14 cholesterol molecules that correspond to existing values. ApoA-I monomer and dimer in structure M can bind in common 6 cholesterol molecules. The values of respective total energy of cholesterol binding for both B and M structures exceed the free energy of cholesterol micellization. Conclusions: Cholesterol dimers may simultaneously interact with extracellular monomer and dimer of lipid-free apoA-I, that accumulate at acid pH in atheroma. The thermodynamically allowed apolipoprotein-cholesterol interaction outside the macrophage may represent a new mechanism of cholesterol transport by apoA-I from atheroma, in addition to ABCA1-mediated cholesterol efflux.

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. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. 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. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.

We studied the mechanism of HDL denaturation with concomitant apoA-I dissociation with HDL preparations from 48 patients with a wide range of plasma HDL-C and evaluated the contribution of lipid-free apoA-I into cholesterol efflux from macrophage, in particular, mediated by cholesterol transporter ABCA1. We prepared HDL by precipitation of apoB-containing lipoproteins by polyethylene glycol and used the chaotropic agent urea to denature HDL preparations. Apo-I dissociation from urea-treated HDL was assessed by the increase of preβ-band fraction with agarose gel electrophoresis followed by electro transfer and immunodetection and by the increase of ABCA1-mediated efflux of fluorescent analogue BODIPY-Cholesterol from RAW 264.7 macrophages. The HDL denaturation is governed by a single transition to fully dissociated apoA-I and the transition cooperativity decreases with increasing HDL-C. The apoA-I release depends on phospholipid concentration of HDL preparation and HDL compositional and structural heterogeneity and is well described by apolipoprotein partition between aqueous and lipid phases. Dissociated apoA-I determines the increase of ABCA1-mediated efflux of BODIPY-Cholesterol from RAW 264.7 macrophages to patient HDL. The increase in apoA-I dissociation is associated with the increase of ABCA1 gene transcript in peripheral blood mononuclear cells from patients. The low level of plasma HDL particles may be compensated by their increased potency for apoA-I release, thus suggesting apoA-I dissociation as a new HDL functional property.

We report the modeling of the interaction of differently self-associated lipid-free apoA-I with cholesterol monomer and tail-to-tail (TT) or face-to-face (FF) cholesterol dimer. Cholesterol dimerization is exploited to reconcile the existing experimental data on cholesterol binding to apoA-I with extremely low critical micelle concentration of cholesterol. Two crystal structures of 1-43 N-truncated apolipoprotein Delta(1-43)A-I tetramer (PDB ID: 1AV1, structure B), 185-243 C-truncated apolipoprotein Delta(185-243)A-I dimer (PDB ID: 3R2P, structure M) were analyzed. Cholesterol monomers bind to multiple binding sites in apoA-I monomer, dimer and tetramer with low, moderate and high energy (-10 to -28 kJ/mol with Schrodinger package), still insufficient to overcome the thermodynamic restriction by cholesterol micellization (-52.8 kJ/mol). The binding sites partially coincide with the putative cholesterol-binding motifs. However, apoA-I monomer and dimer existing in structure B, that contain nonoverlapping and non-interacting pairs of binding sites with high affinity for TT and FF cholesterol dimers, can bind in common 14 cholesterol molecules that correspond to existing values. ApoA-I monomer and dimer in structure M can bind in common 6 cholesterol molecules. The values of respective total energy of cholesterol binding up to 64.5 and 67.0 kJ/mol for both B and M structures exceed the free energy of cholesterol micellization. We hypothesize that cholesterol dimers may simultaneously interact with extracellular monomer and dimer of lipid-free apoA-I, that accumulate at acid pH in atheroma. The thermodynamically allowed apolipoprotein-cholesterol interaction outside the macrophage may represent a new mechanism of cholesterol transport by apoA-I from atheroma, in addition to ABCA1-mediated cholesterol efflux.

Известно, что некодирующие регуляторные РНК влияют на функцию генов. Ранее мы обнаружили отрицательную корреляцию уровня холестерина липопротеинов высокой плотности (ХС-ЛВП) с содержанием транскриптов ряда генов, участвующих в метаболизме ЛВП и в атерогенезе. В данной работе проведен поиск циклических РНК генов HDLBP и TNFRSF1A, а также анализ их представленности в мононуклеарных клетках пациентов с различающимся содержанием ХС-ЛВП. С помощью биоинформатического анализа предсказаны сети возможных конкурентных взаимодействий миРНК с мРНК или циклоРНК данных генов. Сделано предположение, что обнаруженные циклические РНК играют роль конкурентных эндогенных молекул, участвующих в регуляции функционирования соответствующих генов. Non-coding regulatory RNAs are known to affect gene function. We found earlier a negative correlation of high-density lipoprotein cholesterol (HDL-C) with transcripts of some genes involved in HDL metabolism and atherogenesis. In this work, we searched for circular RNA of HDLBP and TNFRSF1A genes in mononuclear cells of patients with different level of HDL-C. The network of competitive interactions of siRNAs with mRNA or circRNA of these genes are predicted by bioinformatic analysis. These circRNAs are suggested to function as the competitive endogenous molecules that are involved in the regulation of gene function.

Background and Aims: To evaluate the contribution of HDL charge heterogeneity to the efficiency of cholesterol efflux.

Background and Aims: To reveal the association of HDL-C and cholesterol efflux capacity (CEC) with the transcript level of annotated genes in peripheral blood mononuclear cells (PBMC) and involved in HDL metabolism and atherogenesis.

Background: To reveal the association of plasma level of high density lipoprotein cholesterol (HDL-C) level with the transcript level of annotated genes in peripheral blood mononuclear cells (PBMC) and involved in HDL metabolism and atherogenesis at the absence of morphologically evident coronary stenosis. Methods: Transcript levels of 63 genes in PBMC from 38 male patients 40-60 years without coronary atherosclerosis with widely varied HDL-C level were measured. The protein interactions were analyzed with STRING database. Results: Among 22 HDL-related genes, the transcript levels for 10 genes (ABCA1, BMP1, CUBN, HDLBP, LCAT, LDLR, PRKACB, PRKACG, SCARB1 and ZDHHC8) negatively correlated with HDL-C, while positively for APOA1 gene. Among 41 atherosclerosis-prone genes, the transcript levels for 11 genes (CSF1R, CSF2RB, IL18R1, ITGAM, ITGB3, PRKCQ, SREBF1, TLR5, TLR8, TNFRSF1A and TNFRSF1B) negatively correlated with HDL-C only, not with LDL-C and plasma TG. The protein products efficiently interacted within each cluster while only two intersection nodes existed between clusters. Conclusions: Coordinate regulation of cholesterol influx and efflux in PBMC in atherosclerosis-free subjects with widely varied HDL-C level is suggested. The decreased synthesis and transport of cholesteryl ester to the liver may contribute to hyperalphalipoproteinemia. HDL-C increase is associated with the decrease of expression of innate immunity and inflammation genes. Visualization of 22 responder genes is suggested to be useful in the validation of HDL functionality and atherogenesis even at the absence of morphologically evident coronary stenosis.

Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing ‘biological oxidations’ activate cholesterol efflux and the substances influencing ‘Signaling by GPCR and PTK6’ inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.

Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing 'biological oxidations' activate cholesterol efflux and the substances influencing 'Signaling by GPCR and PTK6' inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.