Target For Atherosclerosis Research Articles

Exploring the mechanism of Zhengxintai Formula for the treatment of coronary heart disease based on network pharmacology.

Zhengxintai Formula (ZXT) has shown good effects in the clinical treatment of coronary atherosclerotic heart disease (CHD). However, its potential molecular mechanism for treating coronary heart disease is still unknown. The Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform and literature reviews were used to determine the active components and targets of the 6 herbs used in ZXT. Next, we searched disease target databases for targets associated with CHD. Secondly, Cytoscape was used to map the "active compounds-target" network, "protein-protein interaction" network, and "compound-target-disease" network. After that, gene ontology analysis and the pathway analysis by the Kyoto Encyclopedia of Genes and Genomes were performed on the targets. Finally, molecular docking between the compounds and the targets was performed to verify their binding ability. The analysis obtained 116 active compounds of ZXT, corresponding to 611 targets. Thousand three hundred forty-five coronary heart disease targets were collected. Obtained 177 potential ZXT targets for coronary artery disease. Gene ontology analysis yielded 734 biological process entries, 84 cellular component entries, and 122 molecular function entries. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed the key pathways such as "Fluid shear stress and atherosclerosis," "Lipid and atherosclerosis", and "PI3K-Akt signaling pathway." The molecular docking results showed good binding between each screened core target and the core components. ZXT fulfills its role in the treatment of CHD through the core components and core targets that have been screened out, but the exact process still needs to be further investigated.

Instrumental variable and colocalization analyses identify endotrophin and HTRA1 as potential therapeutic targets for coronary artery disease

Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease.

IL-1b as a potential biomarker and therapeutic target in coronary artery disease

Abstract Background Current methods for the early detection of coronary artery disease (CAD) are limited, particularly in those without traditional risk factors. CAD remains a significant cause of morbidity and mortality worldwide, despite advances in diagnostics, treatment and prevention. There is a major unmet need for novel, prognostic blood-based CAD biomarkers, applied to diagnostic strategies or trial endpoints, to accelerate the drug development pipeline and improve clinical trial efficiency. Peripheral blood mononuclear cells (PBMCs) are easily accessible and may serve as a potential cell-derived biomarker or a tool in candidate selection in drug discovery. Purpose This study aims to determine if IL-1β secretion from patient-derived monocytes could differ between patients with calcified atherosclerotic CAD compared with those with no calcified disease and serve as a tool in drug screening. Methods PBMCs were isolated from a cohort of 41 BioHEART participants (ACTRN12618001322224) undergoing clinically indicated CT coronary angiography. We compared 23 participants with CAD, as defined by a coronary artery calcium score (CACS) >0 Agatston units (AU) with 18 participants with no calcified CAD, defined as CACS=0 AU. Monocyte enrichment from PBMCs was achieved through a brief period of in vitro incubation, in which monocytes adhered to the culture plate, while non-monocyte cells were removed by washing. Monocytes were split into 3 conditions; incubated with either (a) 0.01% DMSO in PBS (basal, unstimulated), or (b) stimulated with 1 mM BzATP,or (c) following a 30-minute pre-treatment with a novel P2X7 receptor antagonist, PKT100 (1 μM in PBS 0.01% DMSO), stimulated with BzATP (with PKT100 maintained during the stimulation period). The concentration of IL-1β in supernatant was determined by colormetric ELISA detection. Results We demonstrated that monocytes derived from participants with calcified CAD have a significant elevation in IL-1β secretion following ATP stimulation, when compared to baseline (p<0.0001). While baseline concentration of IL-1β did not differ between control and CAD groups, ATP stimulation of monocytes resulted in a 3.40-fold higher IL-1β concentration in the CAD group compared with the control group (p<0.0001). ATP stimulation of the CAD group in the presence of PKT100 markedly reduced the monocyte IL-1β secretion to near baseline concentrations (p<0.0001). Conclusions Here, we have shown for the first time that PBMCs isolated from participants with CAD secrete higher concentrations of IL-1β upon ATP stimulation compared with non-CAD individuals. This response was markedly reduced after treatment with PKT100, confirming a role for the P2X7 receptor in modulating the downstream IL-1β response to ATP signalling. Further studies are required to understand whether a P2X7 receptor antagonist could be a potential treatment of inflammation associated with CAD.ATP stimulation of CAD patient monocytes

Phytochemicals from Piper betle (L.) as Putative Modulators of a Novel Network-Derived Drug Target for Coronary Artery Disease: An In Silico Study

Coronary artery disease (CAD) is a leading cause of death worldwide. Despite effective anti-CAD drugs, the rising mortality suggests that more pharmacological targets need to be discovered to improve treatment effectiveness. This study explores and evaluates traditional medicinal plant (Piper betle (L.)) compounds against a new target identified through protein network analysis. Our network analysis suggests that the GRB2 protein could be a potential target that links most of the pathological pathway-related proteins in CAD. As a result, we evaluated potential compounds from Piper betle (L.) through ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, docking, and molecular dynamics (MDs) simulation against the GRB2. The ADMET screening detected 49 druggable phytochemicals in Piper betle (L.). Further, screening through molecular docking showed that piperbetol has a higher predicted affinity towards the dimeric form of GRB2 (−8.10 kcal/mol) than other analyzed phytochemicals. Additionally, MD simulation demonstrated that piperbetol formed a stable complex with GRB2 during the simulation. In conclusion, piperbetol from Piper betle showed favorable binding with the identified CAD target. Further investigations are needed for pharmaceutical translation.

Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease.

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1. We have shown previously that the fractalkine receptor CX3CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

153-OR: Genetically Supported Therapeutic Targets for Coronary Artery Disease in Diabetes—Evidence from Proteome-Wide Mendelian Randomization

Coronary artery disease (CAD) remains a major burden in people with diabetes. Genome-wide association studies (GWASs) have identified multiple genetic loci, yet most have yet to translate to clinical applications. The aim of this study was to leverage on genetic data to identify novel drug targets for CAD in diabetes. We applied Mendelian randomization (MR) to investigate the causal association of 1677 plasma proteins from 6 large GWASs, and a recently published GWAS of 15,666 individuals with diabetes (including 3968 CAD cases and 11698 controls). 5 of the 6 proteomic studies were selected as discovery MR analysis, and the remaining one as replication MR to validate the top findings. We employed sensitivity analyses, Bayesian colocalization and transcriptome-wide association study (TWAS) to test the validity of MR assumptions and meanwhile prioritized candidates of drug targets using multi-omics layers. We further integrated phenome-wide MR using the summary data from UK Biobank (N≤408 961) studies and clinical evidence based on DrugBank database to detect potential side effects associated with hypothetical therapeutic agents for CAD in diabetes and prioritize them. Our primary discovery MR analysis identified 4 prioritized proteins (F5, LPA, NPPB and TNFRSF11B) with both MR and colocalization evidence. NPPB and TNFRSF11B could be verified by replication MR analysis. Multi-tissue TWAS analysis revealed all 4 targets whose imputed expression was associated with the outcome. No adverse side effects were found for LPA via phenome-wide MR. By combining the putative causal MR signals with clinical evidence, we suggested these 4 drug repurposing opportunities for the treatment of CAD with diabetes that warranted further investigation. In summary, we prioritized 4 potential drug targets for CAD in diabetes. In particular, LPA might represent a promising target for the treatment of CAD in diabetes, with no predicted adverse side effects. Disclosure C.Huang: None. M.Shi: None. G.Yu: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer Inc., Celltrion, Boehringer Ingelheim and Eli Lilly Alliance, Sanofi, Research Support; AstraZeneca, Servier Laboratories, Viatris Inc., Hua Medicine, Merck KGaA, Applied Therapeutics Inc., Lee Powder, Pfizer Inc., Speaker's Bureau; Novartis, Stock/Shareholder; GemVCare Ltd. R.C.Ma: Advisory Panel; AstraZeneca, Merck & Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Research Grants Council of the Hong Kong Special Administrative Region (CU R4012-18); Croucher Foundation

Tumour necrosis factor receptor 1 inhibition and cardiovascular disease: a cis-Mendelian randomization study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute for Health and Care research (NIHR). Background Tumour necrosis factor receptor 1 (TNFR1) is a newly proposed drug target that has emerged from a growing understanding of the inflammatory basis of cardiovascular disease[1]. A range of pre-clinical models and observational data in humans support the potential efficacy of TNFR1 inhibition. However, pre-clinical models are poor predictors of therapeutic efficacy in humans and observational data is inherently vulnerable to confounding and reverse causation[2,3]. Mendelian randomization (MR) is a genetic epidemiological approach that overcome these limitations and are capable of robust causal inference[3], rendering them better able to investigate the potential efficacy of novel drug targets[2]. Purpose To leverage MR to investigate the causal effect of TNFR1 inhibition on the risk of developing coronary artery disease (CAD), ischaemic stroke (IS), atrial fibrillation (AF), and heart failure (HF) (see Figure 1). Methods cis-Mendelian randomization was performed to estimate the causal effect of TNFR1 inhibition (weighted by serum C-reactive protein (CRP) levels) on liability to coronary artery disease (CAD), ischaemic stroke (IS), atrial fibrillation (AF), and heart failure (HF). Anti-TNF therapies are a cornerstone treatment modality for Crohn’s disease and so Crohn’s was included as a positive control to validate the genetic instrument for TNFR1 inhibition. Furthermore, Bayesian colocalization (coloc) was performed to assess the likelihood that a shared causal variant underlies both TNFR1 signalling and each of these four cardiovascular diseases, thus allowing for interrogation of the risk of confounding by linkage disequilibrium in MR estimates[4]. Genetic association estimates were leveraged from the largest genome-wide association studies (GWAS) for which full publicly available summary data were available. Results As expected, a significant cis-MR effect for genetically proxied TNFR1 inhibition was observed for Crohn’s disease (odds ratio (OR) per 1 standard deviation (SD) reduction in CRP = 0.05, 95% CI = 0.01 to 0.28, P = 5.32 x 10-4). However, no evidence of a causal association was observed between genetically proxied TNFR1 inhibition and the odds of developing CAD (OR per SD reduction in CRP = 0.99, 95% CI = 0.55 to 1.76), IS (OR per SD reduction in CRP = 1.55, 95% CI = 0.30 to 8.03), AF (OR per SD reduction in CRP = 1.11, 95% CI = 0.54 to 2.29), or HF (OR per SD reduction in CRP = 1.02, 95% CI = 0.46 to 2.29) (see Figure 2). No evidence of colocalization was observed between TNFR1 signalling and any of these four cardiovascular diseases. Conclusions These findings do not support TNFR1 signalling inhibition as likely to be an efficacious therapeutic target for coronary artery disease, ischaemic stroke, atrial fibrillation, or heart failure.

Genetic Variants Associated with Supernormal Coronary Arteries.

Genetic and medical insights from studies on cardioprotective phenotypes aid the development of novel therapeutics. This study identified genetic variants associated with supernormal coronary arteries using genome-wide association study data and the corresponding genes based on expression quantitative trait loci (eQTL). Study participants were selected from two Korean cohorts according to inclusion criteria that included males with high cardiovascular risk (Framingham risk score ≥ 14, 10-year risk ≥ 16%) but with normal coronary arteries (supernormal group) or coronary artery disease (control group). After screening 12,309 individuals, males meeting the supernormal phenotype (n=72) and age-matched controls (n=94) were enrolled. Genetic variants associated with the supernormal phenotype were identified using Firth's logistic regression, and eQTL was used to evaluate whether the identified variants influence the expression of particular genes in human tissues. Approximately 5 million autosomal variants were tested for association with the supernormal phenotype, and 10 independent loci suggestive of supernormal coronary arteries (p＜5.0 ×10 －5) were identified. The lead variants were seven intergenic single-nucleotide polymorphisms (SNPs), including one near PBX1, and three intronic SNPs, including one in PPFIA4. Of these variants or their proxies, rs9630089, rs6427989, and rs4984694 were associated with expression levels of SLIT1 and ARHGAP19, PPFIA4, and METTL26 in human tissues, respectively. These eQTL results supported their potential biological relevance. This study identified genetic variants and eQTL genes associated with supernormal coronary arteries. These results suggest candidate genes representing potential therapeutic targets for coronary artery disease.

Epicardial Adipose Tissue as an Independent Cardiometabolic Risk Factor for Coronary Artery Disease.

During the last decades, visceral adiposity has been at the forefront of scientific research because of its complex role in the pathogenesis of cardiovascular diseases. Epicardial adipose tissue (EAT) is the visceral lipid compartment between the myocardium and the visceral pericardium. Due to their unobstructed anatomic vicinity, epicardial fat and myocardium are nourished by the same microcirculation. It is widely known that EAT serves as an energy lipid source and thermoregulator for the human heart. In addition to this, epicardial fat exerts highly protective effects since it releases a great variety of anti-inflammatory molecules to the adjacent cardiac muscle. Taking into account the unique properties of human EAT, it is undoubtedly a key factor in cardiac physiology since it facilitates complex heart functions. Under pathological circumstances, however, epicardial fat promotes coronary atherosclerosis in a variety of ways. Therefore, the accurate estimation of epicardial fat thickness and volume could be utilized as an early detecting method and future medication target for coronary artery disease (CAD) elimination. Throughout the years, several therapeutic approaches for dysfunctional human EAT have been proposed. A balanced healthy diet, aerobic and anaerobic physical activity, bariatric surgery, and pharmacological treatment with either traditional or novel antidiabetic and antilipidemic drugs are some of the established medical approaches. In the present article, we review the current knowledge regarding the anatomic and physiological characteristics of epicardial fat. In addition to this, we describe the pathogenic mechanisms which refer to the crosstalk between epicardial fat alteration and coronary arterial atherosclerosis development. Lastly, we present both lifestyle and pharmacological methods as possible treatment options for EAT dysfunction.

TAILS Identifies Candidate Substrates and Biomarkers of ADAMTS7, a Therapeutic Protease Target in Coronary Artery Disease

Loss-of-function mutations in the secreted enzyme ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) are associated with protection for coronary artery disease. ADAMTS7 catalytic inhibition has been proposed as a therapeutic strategy for treating coronary artery disease; however, the lack of an endogenous substrate has hindered the development of activity-based biomarkers. To identify ADAMTS7 extracellular substrates and their cleavage sites relevant to vascular disease, we used TAILS (terminal amine isotopic labeling of substrates), a method for identifying protease-generated neo–N termini. We compared the secreted proteome of vascular smooth muscle and endothelial cells expressing either full-length mouse ADAMTS7 WT, catalytic mutant ADAMTS7 E373Q, or a control luciferase adenovirus. Significantly enriched N-terminal cleavage sites in ADAMTS7 WT samples were compared to the negative control conditions and filtered for stringency, resulting in catalogs of high confidence candidate ADAMTS7 cleavage sites from our three independent TAILS experiments. Within the overlap of these discovery sets, we identified 24 unique cleavage sites from 16 protein substrates, including cleavage sites in EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1/Fibulin-3). The ADAMTS7 TAILS preference for EFEMP1 cleavage at the amino acids 123.124 over the adjacent 124.125 site was validated using both endogenous EFEMP1 and purified EFEMP1 in a binary in vitro cleavage assay. Collectively, our TAILS discovery experiments have uncovered hundreds of potential substrates and cleavage sites to explore disease-related biological substrates and facilitate activity-based ADAMTS7 biomarker development.

Development and Clinical Translation of P2x7 Receptor Antagonists: A Therapeutic Target in Coronary Artery Disease

Development and Clinical Translation of P2x7 Receptor Antagonists: A Therapeutic Target in Coronary Artery Disease

Identification of potential therapeutic targets for coronary artery disease based on protein array and Mendelian Randomization analysis

Abstract Background Currently, coronary artery disease (CAD) is a main cause of mortality worldwide. Exposing the unknown pathogenic mechanism and exploring potential therapeutic targets of CAD is a critical issue in current CAD research. We aimed to identify potential therapeutic target for CAD using 2-sample Mendelian randomization (MR) approach among differential expression proteins between CAD and control group. Methods Serum samples from 16 first-onset CAD patients diagnosed by coronary angiography and 10 non-CAD controls were collected and detected using protein array. We identified differentially expressed proteins based on “DEseq2” R package and found the core module using MCODE plugin in Cytoscape. Proteins in core modules were used as candidate protein for causal inference. Genetic instrument variables (IV) of candidate proteins were extracted from Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS). Two-sample MR was performed to detect the causal association between the candidate proteins and CAD. For the identified protein causally associated with CAD, sensitivity analyses were used to confirm the finding, including using other MR approach, using more stringent instrument variables, and external cohorts for verification. Network MR was performed to explore whether metabolic risk factors for CAD mediated the risk of identified proteins, including indices of lipid metabolism, glucose metabolism, obesity and blood pressure. Mediation analysis was used to measure the effect of mediation. Results A total of 81 differentially expressed protein were found in CAD group compare to control group, among which 3 core functional modules were found. In five candidate proteins with available instrumental variables, only GP73 was causally associated with CAD risk. Per 1 SD increment in genetically determined GP73 level was associated with 12% increased CAD risk (odds ratio: 1.12; 95% confidence interval: 1.06–1.18, FDR<0.001). Sensitivity analysis yielded consistent results. Network MR analysis shows that across metabolic risk factors profiles for CAD, GP73 level was causally associated with low-density lipoprotein cholesterol (LDL-c), glycated hemoglobin (HbA1c) and waist-to-hip ratio (WHR). Besides, LDL-c, HbA1c and WHR serves as mediators in the causal pathway from GP73 to CAD and transmitted 40.4%, 1.4%, and 5.5% of the total effects, respectively. Conclusion Based on protein array and bioinformatics analysis, this study screened out 3 modules that play core functions in the differential expressed proteins. Among the 19 proteins in the core module, there was a causal relationship between circulating GP73 levels and incident CAD, and the causal effect is mainly mediated by lipid metabolism. The results suggest that GP73 can not only be used as a novel biomarker of CAD, but also may provide a new potential therapeutic target for the management of CAD. Funding Acknowledgement Type of funding sources: None. Figure 1

Diagnostic biomarkers and potential drug targets for coronary artery disease as revealed by systematic analysis of lncRNA characteristics.

BackgroundThe expression profile of lncRNAs in coronary artery disease (CAD) patients has not yet been fully explored. Therefore, the current study aimed to investigate lncRNA-based prognostic biomarkers for CAD.MethodsThe expression profiles of lncRNA and messenger RNA (mRNA) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed lncRNA (DElncRNAs) and DEmRNAs were identified from CAD and normal samples, and weighted gene co-expression network analysis (WGCNA) was conducted. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate the principal functions of significantly dysregulated genes. The potential drugs of new CAD-specific genes were identified by network distance method. Receiver operating characteristic (ROC) was used to verify the classification performance of genes.ResultsA total of 512 differentially expressed genes (DEGs) and 308 DElncRNAs were identified from GSE113079 dataset to classify CAD samples. Through WGCNA co-expression analysis, 24 co-expression modules were obtained. A total of 187 DElncRNAs and 253 DEGs were determined from 7 modules correlated with CAD. Functional enrichment analysis showed that these DEGs were mainly related to inflammatory and immune-related pathways. Furthermore, 36 regulatory pairs of significantly shared micro RNAs (miRNAs) were identified as dysregulated lncRNA-mRNA (LRM-CAD), which contained 11 lncRNAs and 33 genes. Compared with a single lncRNA or gene, LRM-CAD showed stronger classification performance [average area under the curve (AUC) =0.958]. We screened 3 potential therapeutic drugs, DB09105, DB12371, and DB12612, a by binding drug-target gene interaction network. Molecular docking verified that the S1PR1 gene bound relatively closely to DB12371 and DB12612. The ROC analysis on external data sets showed that S1PR1, AC012640.4, and S1PR1-AC012640.4 could effectively distinguish CAD samples from control samples.ConclusionsWe provided a transcriptome overview of abnormally expressed lncRNAs in CAD patients and identified novel biomarkers for diagnosing CAD.

Characteristics of circular RNAs expression of peripheral blood mononuclear cells in humans with coronary artery disease.

Circular RNAs (circRNAs) function as promising biomarkers and therapeutic targets for coronary artery disease due to their high stability, covalently closed structure, and potential gene regulation. We aimed to identify the expression profile and role of circular RNAs (circRNAs) in coronary artery disease (CAD). We performed RNA sequence analysis of circRNAs in peripheral blood mononuclear cells of five patients with CAD and five controls. Bioinformatics analyses were adopted to explore biological functions of differentially expressed circRNAs. The miRanda and TargetScan tools were used to predict the microRNA (miRNA)-targeting interactions and to construct a triple network of differentially expressed gene-circRNA-miRNA-mRNA. In total, 13,160 downregulated and 12,905 upregulated circRNAs were identified in CAD. A gene ontology annotation analysis showed that genes in the network were involved in organelle organization, cell cycle, mitotic cycle, and cellular metabolic process. Parental genes of the 10 dysregulated circRNAs were involved in metabolism and protein modification, and these circRNAs might regulate gene expression associated with CAD via miRNA sponges. As potential competing endogenous RNAs (ceRNAs), dysregulated circRNAs may be involved in the pathogenesis of CAD, which provides new insights into the diagnosis and prognosis of coronary artery disease.

System Genetics Including Causal Inference Identify Immune Targets for Coronary Artery Disease and the Lifespan.

Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference. Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian randomization to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells. Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in Mendelian randomization. In multivariable Mendelian randomization, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. FLT1 and CCR5 were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages (GPX1, C4orf3) and involved in ligand-receptor interactions (CCR5). We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations, and single-cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.

Intrinsic transcriptomic sex differences in human endothelial cells at birth and in adults are associated with coronary artery disease targets

Sex differences in endothelial cell (EC) biology may reflect intrinsic differences driven by chromosomes or sex steroid exposure and gender differences accumulated over life. We analysed EC gene expression data from boy–girl twins at birth and in non-twin adults to detect sex differences at different stages of life, and show that 14–25% of the EC transcriptome is sex-biased. By combining data from both stages of life, we identified sex differences that are present at birth and maintained throughout life, and those that are acquired over life. Promisingly, we found that genes that present with an acquired sex difference in ECs are more likely to be targets of sex steroids. Annotating both gene sets with data from multiple genome-wide association studies (GWAS) revealed that genes with an intrinsic sex difference in ECs are enriched for coronary artery disease GWAS hits. This study underscores the need for treating sex as a biological variable.

NFAT activating protein with ITAM motif 1 (NFAM1) is upregulated on circulating monocytes in coronary artery disease and potentially correlated with monocyte chemotaxis

Background and aimsCirculating monocytes have been proven to be critical mediators in the propagation and progression of atherosclerosis and myocardial infarction. The present study was designed to characterise a new transmembrane protein—NFAT activating protein with ITAM motif 1 (NFAM1)—on monocytes and uncover the potential effects and underlying mechanisms in coronary artery disease. MethodsMonocytes from a population of four controls, five stable coronary artery disease patients and five acute coronary syndrome patients were isolated for RNA sequencing. A potential monocyte biomarker molecule was discovered and then validated with a group of 79 controls, 70 stable coronary artery disease patients and 183 acute coronary syndrome patients. A stable cell line was generated as an in vitro model to determine chemotaxis migration and chemokine receptor expression. ResultsNFAM1 was identified through RNA sequencing analysis. The validation results confirmed that NFAM1 expression on monocytes was significantly increased by coronary artery disease status. A higher expression level of NFAM1 on classical and intermediate monocytes was observed compared with that on nonclassical monocytes. As shown in the in vitro cell model, knockdown of NFAM1 significantly attenuated chemotactic migration of monocytes by downregulating chemokine receptor expression and the p38 MAPK signalling pathway. Multivariable regression analysis of a group of 16 individuals suggested that NFAM1 was positively correlated with CCR2 expression. ConclusionsThe present study reported for the first time that distinctive alterations of NFAM1 expression on monocytes may correlate with atherosclerosis pathobiology and serve as a potential monocyte biomarker and therapeutic target for coronary artery disease.

Proteomic landscape of human coronary artery atherosclerosis.

In order to investigate novel biomarkers for the detection of coronary artery disease for effective therapeutic targets, a comprehensive understanding of the protein networks and protein expression abundance in coronary artery samples is required. This was established by means of liquid chromatography (LC)-mass spectrometry (MS)/MS analysis in the present study. A total of 20 human coronary artery specimens from 2 autopsied adults were employed in the present study. The natural history and histological classification of the atherosclerotic lesions of the coronary artery samples were analyzed by hematoxylin and eosin (H&E) staining, and the human coronary arterial proteome and proteomics features were characterized by MS analysis. The present study identified 2,135 proteins in the 20 coronary artery segments samples from the 2 cases. Combined with the results of H&E staining of the coronary artery samples, a total of 174 proteins, including 4 upregulated proteins and 164 downregulated proteins (excluding 6 proteins with inconsistent expression tendencies), were shown to be associated with coronary artery disease. In addition, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment of the differentially expressed proteins revealed that the mitochondrial energy metabolism may be responsible for the occurrence and development of coronary artery atherosclerosis. The human coronary arterial proteome can be considered as a complex network whose architectural characteristics vary considerably as a function of the presence or absence, and histological classification of coronary artery atherosclerosis. These data thus suggest that the prevention of mitochondrial dysfunction via the retrieval of the mitochondrial associated proteins expression may be a promising target in coronary artery disease.

The NLRP3 Inflammasome as a promising target for Coronary Artery Disease: Current and Pipeline NLRP3 Inhibitors

The NLRP3 Inflammasome as a promising target for Coronary Artery Disease: Current and Pipeline NLRP3 Inhibitors

The NLRP3 Inflammasome as a promising target for Coronary Artery Disease: Current and Pipeline NLRP3 Inhibitors

Coronary Artery Disease (CAD) represents a major health burden worldwide. It is driven by chronic inflammation of the arterial vasculature supplying the heart, in response to pro-inflammatory assaults such as high LDL cholesterol. The resultant atherosclerosis can cause occlusive disease and acute cardiovascular events.