ABSTRACT
Acute coronary heart disease (CHD) is mainly caused by the rupture of an unstable atherosclerotic plaque. Many different factors can cause stenosis or even occlusion of the coronary artery lumen, such as vasculitis and platelet aggregation. Our study was performed to assess the association between PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphisms and the risk of CHD, as well as the association between studied polymorphisms and selected clinical parameters affecting the risk of developing ischemic heart disease. A total of 232 patients with unstable angina were enrolled in this study. There were no statistically significant differences in the PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphism distributions between the total study and control groups. Total cholesterol plasma levels were significantly higher in patients with the PON1 rs662 TT genotype compared to those with the CC+TC genotypes, as well as in patients with the PON1 rs854560 TT genotype compared to those with the AA+AT genotypes. LDL plasma levels were significantly increased in patients with the PON1 rs854560 TT genotype compared to those with the AA+AT genotypes. Plasma levels of HDL were significantly decreased in patients with the TRIB1 rs17321515 AA+AG genotypes compared to those with the GG genotype, as well as in patients with the TRIB1 rs2954029 AA+AT genotypes compared to those with the TT genotype. Our results suggest that the analysed polymorphisms are not risk factors for unstable angina in the Polish population. However, the results of this study indicate an association between the PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphisms with lipid parameters in patients with coronary artery disease.
Subject(s)
Angina, Unstable , Aryldialkylphosphatase , Intracellular Signaling Peptides and Proteins , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases , Humans , Male , Female , Aryldialkylphosphatase/genetics , Middle Aged , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Angina, Unstable/genetics , Angina, Unstable/blood , Intracellular Signaling Peptides and Proteins/genetics , Aged , Genetic Predisposition to Disease , Lipids/blood , Case-Control Studies , GenotypeABSTRACT
BACKGROUND: Acute Coronary Syndrome (ACS) stands as a significant contributor to cardiovascular mortality, necessitating improved diagnostic tools for early detection and tailored therapeutic interventions. Current diagnostic modalities, exhibit limitations in sensitivity and specificity, urging the quest for novel biomarkers to enhance discrimination of the different stages of ACS including unstable angina, Non-ST-segment Elevation Myocardial Infarction (NSTEMI), and ST-segment Elevation Myocardial Infarction (STEMI). METHODS: This study investigated the potential of a plasma-circulating multi-noncoding RNA (ncRNA) panel, comprising four miRNAs (miR-182-5p, miR-23a-3p, miR-146a-5p, and miR-183-5p) and three lncRNAs (SNHG15, SNHG5, and RMRP), selected based on their intricate involvement in ACS pathogenesis and signaling pathways regulating post-myocardial infarction (MI) processes. The differential expression of these ncRNAs was validated in sera of ACS patients and healthy controls via real-time polymerase chain reaction (RT-PCR). RESULTS: Analysis revealed a marked upregulation of the multi-ncRNAs panel in ACS patients. Notably, miRNA-182-5p and lncRNA-RMRP exhibited exceptional discriminatory power, indicated by the high area under the curve (AUC) values (0.990 and 0.980, respectively). Importantly, this panel displayed superior efficacy in discriminating between STEMI and NSTEMI, outperforming conventional biomarkers like creatine kinase-MB and cardiac troponins. Additionally, the four miRNAs and lncRNA RMRP showcased remarkable proficiency in distinguishing between STEMI and unstable angina. CONCLUSION: The findings underscore the promising potential of the multi-ncRNA panel as a robust tool for early ACS detection, and precise differentiation among ACS subtypes, and as a potential therapeutic target.
Subject(s)
Acute Coronary Syndrome , MicroRNAs , Myocardial Infarction , Non-ST Elevated Myocardial Infarction , RNA, Long Noncoding , ST Elevation Myocardial Infarction , Humans , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/genetics , ST Elevation Myocardial Infarction/diagnosis , ST Elevation Myocardial Infarction/therapy , Non-ST Elevated Myocardial Infarction/diagnosis , Non-ST Elevated Myocardial Infarction/pathology , RNA, Long Noncoding/genetics , MicroRNAs/genetics , Myocardial Infarction/diagnosis , Myocardial Infarction/genetics , Biomarkers , Angina, Unstable/diagnosis , Angina, Unstable/geneticsABSTRACT
The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. The Nourin protein is rapidly expressed in patients with acute coronary syndrome (ACS) (UA and acute myocardial infarction (AMI)). MicroRNAs regulate gene expression through mRNA binding and, thus, may represent potential biomarkers. We initially identified miR-137 and miR-106b and conducted a clinical validation, which demonstrated that they were highly upregulated in ACS patients, but not in healthy subjects and non-ACS controls. Using integrated comprehensive bioinformatics analysis, the present study confirms that the Nourin protein targets miR-137 and miR-106b, which are linked to myocardial ischemia and inflammation associated with ACS. Molecular docking demonstrated robust interactions between the Nourin protein and miR137/hsa-miR-106b, involving hydrogen bonds and hydrophobic interactions, with -10 kcal/mol binding energy. I-TASSER generated Nourin analogs, with the top 10 chosen for structural insights. Antigenic regions and MHCII epitopes within the Nourin SPGADGNGGEAMPGG sequence showed strong binding to HLA-DR/DQ alleles. The Cytoscape network revealed interactions of -miR137/hsa-miR--106b and Phosphatase and tensin homolog (PTEN) in myocardial ischemia. RNA Composer predicted the secondary structure of miR-106b. Schrödinger software identified key Nourin-RNA interactions critical for complex stability. The study identifies miR-137 and miR-106b as potential ACS diagnostic and therapeutic targets. This research underscores the potential of miRNAs targeting Nourin for precision ACS intervention. The analysis leverages RNA Composer, Schrödinger, and I-TASSER tools to explore interactions and structural insights. Robust Nourin-miRNA interactions are established, bolstering the case for miRNA-based interventions in ischemic injury. In conclusion, the study contributes to UA and AMI diagnosis strategies through bioinformatics-guided exploration of Nourin-targeting miRNAs. Supported by comprehensive molecular analysis, the hypoxia-induced miR-137 for cell apoptosis (a marker of cell damage) and the inflammation-induced miR-106b (a marker of inflammation) confirmed their potential clinical use as diagnostic biomarkers. This research reinforces the growing role of miR-137/hsa-miR-106b in the early diagnosis of myocardial ischemia in unstable angina patients.
Subject(s)
Acute Coronary Syndrome , Coronary Artery Disease , MicroRNAs , Myocardial Infarction , Humans , Molecular Docking Simulation , MicroRNAs/metabolism , Angina, Unstable/diagnosis , Angina, Unstable/genetics , Myocardial Infarction/diagnosis , Myocardial Infarction/genetics , Biomarkers , Inflammation/metabolismABSTRACT
Coronary artery disease (CAD) is a leading cause of mortality worldwide. In this study, we aimed to assess the potential of plasma long non-coding RNAs (lncRNAs) LIPCAR and MALAT1 and microRNAs (miRNAs) miR-142-3p and miR-155-5p to discriminate unstable CAD patients from stable ones. 23 stable angina (SA), 21 unstable angina (UA), and 50 ST-segment elevation myocardial infarction (STEMI) patients were enrolled; their plasma was collected. ncRNA plasma levels were evaluated using RT-qPCR. All measured ncRNA levels were significantly increased in UA patients' plasma compared to SA patients' plasma and in STEMI-with major adverse cardiovascular event (MACE) patients' plasma vs. STEMI-without MACE patients' plasma. ROC analysis showed that increased levels of LIPCAR and MALAT1 were associated with UA, and the prognostic model improved with the addition of miR-155-5p levels. The assessed lncRNAs discriminated between hyperglycemic (HG) and normoglycemic (NG) UA patients, and they were associated with MACE incidence in STEMI patients; this prediction was improved by the addition of miR-142-3p levels to the ROC multivariate model. We propose LIPCAR and MALAT1 as effective diagnostic markers for vulnerable CAD, their association with HG in UA patients, and as robust predictors for unfavorable evolution of STEMI patients.
Subject(s)
Acute Coronary Syndrome , Coronary Artery Disease , MicroRNAs , RNA, Long Noncoding , ST Elevation Myocardial Infarction , Humans , Acute Coronary Syndrome/genetics , Angina, Unstable/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , ST Elevation Myocardial Infarction/geneticsABSTRACT
BACKGROUND: Atherosclerosis plays an important role in the pathophysiology of acute coronary syndrome (ACS). CD36 is a scavenger receptor involved in lipid metabolism. Some single-nucleotide variants in the non-coding region could indirectly alter the expression and the function of the protein. OBJECTIVE: The aim of this study was to investigate the gene and protein expression associated with CD36 variants (rs1194182;C > G; rs1049654;C > A, rs1334512;G > T, and rs3211892;G > A) in ACS patients from the western Mexican population. METHODS: We recruited 310 ACS patients and 308 subjects in the control group (CG). Genotyping was determined by TaqMan SNP genotyping assays. CD36 expression at the mRNA level was quantified by TaqMan gene expression assays. Soluble CD36 (sCD36) was measured by enzyme-linked immunosorbent assay. RESULTS: We show that rs1194182G > C variant provides a protective effect with a 1.7-fold lower susceptibility to develop ACS (p = 0.03); however, this association was masked by diabetes and dyslipidemia. We observed a higher sCD36 concentration in patient with ST-segment elevation myocardial infarction (STEMI) compared with patients with unstable angina (UA) (p = 0.038). Likewise, in diabetic patients versus non-diabetic (p < 0.001). We observed in patients an increase in CD36 mRNA expression (1.91 times higher) than in the CG (p = 0.02). CONCLUSION: The rs1194182 seems to be associated with diabetes in a risky manner, in ACS patients and protective for dyslipidemia in both groups. The concentration of sCD36 seems to be associated with the clinical spectrum of the ACS patients and the presence of diabetes, since patients with STEMI present significantly elevated level compared with UA.
Subject(s)
Acute Coronary Syndrome , CD36 Antigens , Dyslipidemias , ST Elevation Myocardial Infarction , Acute Coronary Syndrome/genetics , Angina, Unstable/genetics , CD36 Antigens/genetics , Gene Expression , Humans , RNA, Messenger/genetics , ST Elevation Myocardial Infarction/geneticsABSTRACT
MicroRNAs (miRNAs) are important types of noncoding RNAs, and there is a lack of holistic and systematic understanding of the functions they play in disease. We proposed a research strategy, including two parts network analysis and network modelling, to analyze, model, and predict the regulatory network of miRNAs from a network perspective, using unstable angina pectoris as an example. In the network analysis section, we proposed the WGCNA & SimCluster method using both correlation and similarity to find hub miRNAs, and validation on two datasets showed better results than the methods using correlation or similarity alone. In the network modelling section, we used six knowledge graph or graph neural network models for link prediction of three types of edges and multilabel classification of two types of nodes. Comparative experiments showed that the RotatE model was a good model for link prediction, while the RGCN model was the best model for multilabel classification. Potential target genes were predicted for hub miRNAs and validation of hub miRNA-target gene interactions, target genes as biomarkers and target gene functions were performed using a three-step validation approach. In conclusion, our study provides a new strategy to analyze and model miRNA regulatory networks.
Subject(s)
Gene Regulatory Networks , MicroRNAs , Humans , MicroRNAs/genetics , Neural Networks, Computer , Angina, Unstable/genetics , Computational BiologyABSTRACT
Gut microbiota plays an important role in coronary heart disease, but its compositional and functional changes in unstable angina (UA) remain unexplored. We performed metagenomic sequencing of 133 newly diagnosed UA patients and 133 sex- and age-matched controls, and profiled the fecal and plasma metabolomes in 30 case-control pairs. The alpha diversity of gut microbiota was increased in UA patients: the adjusted odds ratios (ORs) per standard deviation increase in Shannon and Simpson indices were 1.30 (95% confidence interval, 1.01-1.70) and 1.36 (1.05-1.81), respectively. Two common species (depleted Klebsiella pneumoniae and enriched Streptococcus parasanguinis; P ≤ 0.002) and three rare species (depleted Weissella confusa, enriched Granulicatella adiacens and Erysipelotrichaceae bacterium 6_1_45; P ≤ 0.005) were associated with UA. The UA-associated gut microbiota was depleted in the pathway of L-phenylalanine degradation (P = 0.001), primarily contributed by Klebsiella pneumoniae. Consistently, we found increased circulating phenylalanine in UA patients (OR = 2.76 [1.17-8.16]). Moreover, Streptococcusparasanguinis was negatively correlated with fecal citrulline (Spearman's rs = -0.470, P = 0.009), a metabolite depleted in UA patients (OR = 0.26 [0.08-0.63]). These findings are informative to help understand the metabolic connection between gut microbiota and UA.
Subject(s)
Gastrointestinal Microbiome , Angina, Unstable/diagnosis , Angina, Unstable/genetics , Feces , Gastrointestinal Microbiome/genetics , Humans , MetabolomeABSTRACT
BACKGROUND: Acute coronary syndrome (ACS) is a complex cardiovascular disease whose development involves the dysregulation of adaptive immune responses. Though it has been proven that T cells associate with inflammation in the development of ACS, the function of B cells in disease remains unclear. OBJECTIVE: The aim of this study was to reveal the diversity of the B cell receptor (BCR) repertoire of patients with ACS. METHODS: We conducted a pilot study to sequence the immune repertoire of peripheral blood mononuclear cells (PBMCs) from patients with ACS, including acute myocardial infarction (AMI) and unstable angina (UA), and quantitatively characterized BCR repertoires by bioinformatics analysis. RESULTS: We found that patients with AMI and UA had lower BCR repertoire diversity compared with controls with normal coronary arteries (NCA). Lower percentages of productive unique BCR nt sequences and higher percentages of top 200 unique BCR sequences were identified in AMI and UA patients than NCA controls. Patients had various preferential usage of V and J genes from B cell clones in accordance with the disease severity of coronary arteries. AMI patients had distinct CDR3 amino acids, and their frequency differed among patients with ACS. CONCLUSIONS: Our results indicate that differential BCR signatures represent an imprint of distinct repertoires among ACS patients. This study thereby opens up the prospect of studying disease-relevant B cells to better understand and treat ACS.
Subject(s)
Acute Coronary Syndrome/genetics , B-Lymphocytes/metabolism , Leukocytes, Mononuclear/metabolism , Receptors, Antigen, B-Cell/genetics , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/metabolism , Aged , Amino Acid Sequence , Angina, Unstable/genetics , Angina, Unstable/metabolism , Complementarity Determining Regions/genetics , Computational Biology/methods , Coronary Vessels/metabolism , Female , Genetic Variation , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Middle Aged , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Pilot Projects , Receptors, Antigen, B-Cell/metabolismSubject(s)
Angina, Unstable , Interleukin-6 , Angina, Unstable/genetics , Endothelium , Humans , Inflammation/genetics , Interleukin-6/geneticsABSTRACT
BACKGROUND: Increasing evidences suggest that long noncoding RNAs (lncRNAs) play critical roles in the pathogenesis of coronary artery disease (CAD). However, the association between lncRNAs expression profiles and unstable angina (UA) remained poorly known. Thus, the present study aims to investigate expression patterns, biological functions, and diagnostic value of lncRNAs in UA. METHODS: The present study explored the lncRNA and mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of UA patients and normal coronary artery (NCA) controls using RNA-seq. The biological function of differentially expressed lncRNAs was analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The expression of the selected lncRNAs was validated in another 44 UA patients and 46 NCA controls. Receiver operating characteristic curve (ROC) was performed to evaluate the diagnostic value of lncRNAs for UA. RESULTS: A total of 98 lncRNAs and 615 mRNAs were observed differentially expressed in PBMCs of UA patients as compared to NCA controls. The 10 most upregulated lncRNAs were LNC_000226, DANCR, RP1-167A14.2, LNC_002091, LNC_001526, LNC_001165, LNC_002772, LNC_000088, LNC_001226, and FAM157C, and the 10 most downregulated lncRNAs were RP11-734I18.1, RP11-185E8.1, RP11-360I2.1, LNC_001302, LNC_001287, RN7SL471P, LNC_000914, LINC01506, RP11-160E2.6, and LNC_000995. LNC_000226 and MALAT1 have high area under the curve values (AUC) for distinguishing UA from NCA patients (0.810 and 0.799, respectively), and the combination of MALAT1 and LNC_000226 increased the AUC value to 0.878. CONCLUSIONS: The present study added our understanding about the lncRNA expression profile in UA patients and provided potential biomarkers for the diagnosis of UA.
Subject(s)
Angina, Unstable , RNA, Long Noncoding , Transcriptome/genetics , Aged , Angina, Unstable/diagnosis , Angina, Unstable/genetics , Angina, Unstable/metabolism , Biomarkers/blood , Female , Humans , Male , Middle Aged , RNA, Long Noncoding/blood , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolismABSTRACT
Acute coronary syndrome (ACS) is a complex syndrome of clinical symptoms. In order to accurately diagnose the type of disease in ACS patients, this study is aimed at exploring the differentially expressed genes (DEGs) and biological pathways between acute myocardial infarction (AMI) and unstable angina (UA). The GSE29111 and GSE60993 datasets containing microarray data from AMI and UA patients were downloaded from the Gene Expression Omnibus (GEO) database. DEG analysis of these 2 datasets is performed using the "limma" package in R software. DEGs were also analyzed using protein-protein interaction (PPI), Molecular Complex Detection (MCODE) algorithm, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Correlation analysis and "cytoHubba" were used to analyze the hub genes. A total of 286 DEGs were obtained from GSE29111 and GSE60993, including 132 upregulated genes and 154 downregulated genes. Subsequent comprehensive analysis identified 20 key genes that may be related to the occurrence and development of AMI and UA and were involved in the inflammatory response, interaction of neuroactive ligand-receptor, calcium signaling pathway, inflammatory mediator regulation of TRP channels, viral protein interaction with cytokine and cytokine receptor, human cytomegalovirus infection, and cytokine-cytokine receptor interaction pathway. The integrated bioinformatical analysis could improve our understanding of DEGs between AMI and UA. The results of this study might provide a new perspective and reference for the early diagnosis and treatment of ACS.
Subject(s)
Angina, Unstable/genetics , Computational Biology , Data Mining , Gene Expression Profiling , Gene Expression Regulation , Myocardial Infarction/genetics , Cluster Analysis , Databases, Genetic , Gene Ontology , Humans , Protein Interaction Maps/geneticsABSTRACT
OBJECTIVE: The aim of the study was to evaluate the DNA and chromosomal damage in peripheral blood lymphocytes (PBLs) of patients with acute coronary syndrome (ACS) and to explore the effect of coronary angiographies in these patients. METHODS: The study included ACS patients who underwent a coronary angiography (CAG) and healthy controls. The ACS sample was divided into two groups: patients with unstable angina pectoris (UAP) and acute myocardial infarction (AMI). The frequency of DNA damage [expressed as genetic damage index (GDI)] was analyzed using the comet assay pre- and post-CAG. Chromosomal aberrations were measured as micronuclei (MNs) frequency using the cytokinesis-block MN (CBMN) assay. Additionally, detailed anamnestic data were taken from the each patient. RESULTS: Increased levels of DNA and chromosomal damage have been revealed in ACS patients compared to the healthy controls. GDI values were also significantly higher in AMI patients than in UAP patients. A highly significant increase of DNA damage was also observed in all patients post-CAG. There was significantly higher MN frequency and significantly lower nuclear division index (NDI) in AMI patients than in UAP patients' pre-CAG. After CAG, there was no significant difference in MN frequencies and NDI values between UAP and AMI patients. CONCLUSION: Correlated with disease severity, our results showed that AMI patients have higher levels of both DNA and chromosomal damage in PBLs compared to UAP patients. The increased level of genome instability was especially evident post-CAG compared to the observed damage pre-CAG.
Subject(s)
Acute Coronary Syndrome , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/genetics , Angina, Unstable/diagnostic imaging , Angina, Unstable/genetics , Coronary Angiography , DNA , Humans , LymphocytesABSTRACT
BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. OBJECTIVES: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats". METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. CONCLUSIONS: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.
Subject(s)
Imidazolidines/pharmacology , MicroRNAs/genetics , Phosphocreatine/analogs & derivatives , Angina, Unstable/genetics , Animals , Biomarkers, Pharmacological , Heart Failure/drug therapy , Heart Failure/genetics , Humans , Imidazolidines/metabolism , Isoproterenol/therapeutic use , Male , MicroRNAs/metabolism , Myocardial Infarction/genetics , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Phosphocreatine/genetics , Phosphocreatine/metabolism , Phosphocreatine/pharmacology , RNA, Messenger/metabolism , Rats , Rats, WistarABSTRACT
BACKGROUND: Currently, no blood biomarkers exist that can diagnose unstable angina (UA) patients. Nourin is an early inflammatory mediator rapidly released within 5 min by reversible ischemic myocardium, and if ischemia persists, it is also released by necrosis. Nourin is elevated in acute coronary syndrome (ACS) patients but not in symptomatic noncardiac and healthy subjects. Recently, circulating microRNAs (miRNAs) have been established as markers of disease, including cardiac injury and inflammation. OBJECTIVES: To profile and validate the potential diagnostic value of Nourin-dependent miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) as early biomarkers in suspected UA patients and to investigate the association of their target and regulating genes. METHODS: Using Nourin amino acid sequence, an integrated bioinformatics analysis was conducted. Analysis indicated that Nourin is a direct target for miR-137 and miR-106b-5p in myocardial ischemic injury. Two linked molecular networks of lncRNA/miRNAs/mRNAs were also retrieved, including CTB89H12.4/miR-137/FTHL-17 and CTB89H12.4/miR-106b-5p/ANAPC11. Gene expression profiling was assessed in serum samples collected at presentation to an emergency department (ED) from: (1) UA patients (n = 30) (confirmed by invasive coronary angiography with stenosis greater than 50% and troponin level below the clinical decision limit); (2) patients with acute ST elevation myocardial infarction (STEMI) (n = 16) (confirmed by persistent ST-segment changes and elevated troponin level); and 3) healthy subjects (n = 16). RESULTS: Gene expression profiles showed that miR-137 and miR-106b-5p were significantly upregulated by 1382-fold and 192-fold in UA compared to healthy, and by 2.5-fold and 4.6-fold in STEMI compared to UA, respectively. Healthy subjects showed minimal expression profile. Receiver operator characteristics (ROC) analysis revealed that the two miRNAs were sensitive and specific biomarkers for assessment of UA and STEMI patients. Additionally, Spearman's correlation analysis revealed a significant association of miRNAs with the associated mRNA targets and the regulating lncRNA. CONCLUSIONS: Nourin-dependent gene expression of miR-137 and miR-106b-5p are novel blood-based biomarkers that can diagnose UA and STEMI patients at presentation and stratify severity of myocardial ischemia, with higher expression in STEMI compared to UA. Early diagnosis of suspected UA patients using the novel Nourin biomarkers is key for initiating guideline-based therapy that improves patients' health outcomes.
Subject(s)
Angina, Unstable/diagnosis , Angina, Unstable/genetics , Early Diagnosis , MicroRNAs/metabolism , Acute Coronary Syndrome/genetics , Apoferritins/genetics , Apoferritins/metabolism , Case-Control Studies , Female , Humans , Male , MicroRNAs/genetics , Middle Aged , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , ROC CurveABSTRACT
INTRODUCTION: Coronary artery disease (CAD) is a significant public health problem because it is one of the major causes of death worldwide. Several studies have investigated the associations between CAD and polymorphisms in genes connected with platelet aggregation and the risk of venous thromboembolism. AIM: In this study, we examined the associations between polymorphisms in GP6 (rs1671152), PEAR1A (rs12566888), MRVI1 (rs7940646), PIK3CG (rs342286), JMJD1C (rs10761741), SHH (rs2363910), and CAD in the form of unstable angina as well as selected clinical and biochemical parameters. The study enrolled 246 patients with diagnosed unstable angina and 189 healthy controls. RESULTS: There were no significant differences in the distribution of the studied polymorphisms between the patients with unstable angina and the controls. In patients with the GP6 rs1671152 GG genotype, we observed increased BMI values and an increased frequency of type 2 diabetes diagnosis. CONCLUSIONS: The results of this study suggest a lack of association between GP6 (rs1671152), PEAR1A (rs12566888), MRVI1 (rs7940646), PIK3CG (rs342286), JMJD1C (rs10761741), SHH (rs2363910), and unstable angina. The results indicate an association between GP6 (rs1671152) and type 2 diabetes.
Subject(s)
Angina, Unstable , Diabetes Mellitus, Type 2 , Genotype , Polymorphism, Single Nucleotide , Aged , Angina, Unstable/genetics , Class Ib Phosphatidylinositol 3-Kinase , Hedgehog Proteins , Humans , Jumonji Domain-Containing Histone Demethylases , Middle Aged , Oxidoreductases, N-Demethylating , Platelet AggregationABSTRACT
OBJECTIVE: To explore the possible role of miR-499a-3p in the function of primary human umbilical vein endothelial cells (HUVECs) and the expression of ADAM10 in primary HUVEC. METHOD: miR-499a-3p was first transfected into primary HUVECs via lentivirus vector. The viability, proliferation, and migration of stable transfected primary HUVEC were then determined by flow cytometry, CCK8 assays, scratch tests, and Transwell tests. The transcription of miR-499a-3p and ADAM10 was examined by reverse transcription-polymerase chain reaction (RT-PCR), and the expression of ADAM10 was examined by Western blot (WB). RESULTS: After transfection, miR-499a-3p transcription was significantly increased (P < 0.01), compared to the blank and nonspecific control (NC) groups, while both ADAM10 transcription and expression were significantly decreased (P < 0.05). In contrast, in the inhibitors group, miR-499a-3p transcription was significantly reduced (P < 0.05) whereas both ADAM10 transcription and expression were significantly increased (P < 0.05). The viability, proliferation, and migration of primary HUVECs were significantly impaired (P < 0.05) by the transfection of miR-499a-3p but enhanced by miR-499a-3p inhibitors (P < 0.05). CONCLUSIONS: Upregulation of miR-499a-3p transcription will inhibit the expression of ADAM10 in HUVECs; cell migration and proliferation, however, promote apoptosis. And reverse effects were established by downregulation of miR-499a-3p transcription. All these effects may be achieved by regulating the transcription and expression of ADAM10. These results combined suggested that miR-499a-3p may affect the proliferation, migration, and apoptosis of endothelial cells and regulate AS by regulating ADAM10. miR-499a-3p may become a candidate biomarker for the diagnosis of unstable angina pectoris (UA).
Subject(s)
Human Umbilical Vein Endothelial Cells/metabolism , MicroRNAs/genetics , ADAM10 Protein/genetics , ADAM10 Protein/metabolism , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Angina, Unstable/diagnosis , Angina, Unstable/etiology , Angina, Unstable/genetics , Apoptosis/genetics , Atherosclerosis/etiology , Atherosclerosis/genetics , Atherosclerosis/pathology , Cell Movement/genetics , Cell Proliferation/genetics , Cell Survival/genetics , Down-Regulation , Gene Expression , Genetic Vectors , Human Umbilical Vein Endothelial Cells/cytology , Humans , Lentivirus/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , MicroRNAs/metabolism , Transfection , Up-RegulationABSTRACT
OBJECTIVE: Mannose-binding lectin (MBL) is linked to risk of cardiovascular disease (CVD) in diabetes, but the nature of the association is unclear. We investigated the association between MBL and the risk of cardiovascular events (CVE) and all-cause mortality in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort study of 7,588 patients with type 2 diabetes, we measured serum MBL in 7,305 patients and performed MBL expression genotyping in 3,043 patients. We grouped serum MBL and MBL expression genotypes into three categories: low, intermediate, and high. Outcomes were CVE (myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death) and all-cause mortality. The association with outcomes was examined by spline and Cox regression analyses. RESULTS: Serum MBL and CVE showed a U-shaped association. Compared with the intermediate serum MBL category, the adjusted hazard ratio (HR) for CVE was 1.82 (95% CI 1.34-2.46) for the low-MBL category and 1.48 (95% CI 1.14-1.92) for the high-MBL category. We found a similar U-shaped association for all-cause mortality, but with lower risk estimates. Compared with the intermediate MBL expression genotype, the adjusted HR for CVE was 1.40 (95% CI 0.87-2.25) for the low-expression genotype and 1.44 (95% CI 1.01-2.06) for the high-expression genotype. MBL expression genotype was not associated with all-cause mortality. CONCLUSIONS: Both serum MBL and MBL expression genotype showed a U-shaped association with CVE risk in individuals with type 2 diabetes. Our findings suggest that serum MBL is a risk factor for CVD in this population.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Diabetic Angiopathies/genetics , Diabetic Angiopathies/mortality , Mannose-Binding Lectin/genetics , Aged , Angina, Unstable/complications , Angina, Unstable/genetics , Angina, Unstable/mortality , Cohort Studies , Denmark/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/mortality , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Mannose-Binding Lectin/blood , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/genetics , Myocardial Infarction/mortality , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
BACKGROUND: This study aims to investigate the T-cell receptor (TCR) repertoire in patients with acute coronary syndrome (ACS). METHODS: The TCR repertoires of 9 unstable angina patients (UA), 14 acute myocardial infarction patients (AMI) and 9 normal coronary artery (NCA) patients were profiled using high-throughput sequencing (HTS). The clonal diversity of the TCR repertoires in different groups was analyzed, as well as the frequencies of variable (V), diversity (D) and joining(J) gene segments. RESULTS: ACS patients including UA and AMI, showed reduced TCRß diversity than NCA patients. ACS patients presented higher levels of clonal expansion. The clonotype overlap of complementarity determining region 3(CDR3) was significantly varied between different groups. A total of 10 V genes and 1 J gene were differently utilized between ACS and NCA patients. We identified some shared CDR3 amino acid sequences that were presented in ACS but not in NCA patients. CONCLUSIONS: This study revealed the distinct TCR repertoires in patients with ACS and demonstrated the presence of disease associated T-cell clonotypes. These findings suggested a role of T cells in ACS and provided a new way to explore the mechanisms of ACS.
Subject(s)
Acute Coronary Syndrome/genetics , Angina, Unstable/genetics , Genes, T-Cell Receptor , High-Throughput Nucleotide Sequencing , Myocardial Infarction/genetics , T-Lymphocytes/immunology , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/immunology , Aged , Angina, Unstable/diagnosis , Angina, Unstable/immunology , Case-Control Studies , China , Complementarity Determining Regions/genetics , Female , Genes, T-Cell Receptor beta/genetics , Humans , Immunoglobulin Variable Region , Male , Middle Aged , Myocardial Infarction/diagnosis , Myocardial Infarction/immunologyABSTRACT
Acute coronary syndrome occurs when the heart muscle does not receive adequate oxygen and nutrients in a timely manner. Acute coronary syndromes are primarily due to atherosclerosis of the coronary arteries, i.e., coronary heart disease. Nitric oxide (NO) is synthesised from L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme, nitric oxide synthase (NOS), which mediates endothelium-dependent vasodilatation. Endothelial nitric oxide synthase (eNOS) is predominantly expressed in endothelial cells. Three NOS isoforms have been detected in different tissue: (1) neuronal NOS (nNOS) (NOS1), (2) eNOS (NOS2), and (3) inducible NOS (iNOS) (NOS3). These isoforms are encoded by three different genes. NOS3 is located on chromosome 7q35-36 and contains 26 exons. Previous studies have suggested that NOS3 polymorphisms may be associated with acute coronary syndromes. Therefore, the aim of the study was to examine the associations between NOS3 rs1799983 (894G/T)andrs2070744 (-786T/C) polymorphisms and unstable angina. This study included 246 patients with unstable angina, as confirmed by coronary angiography. We also included 189 healthy controls who were also assessed by this technique. There were no significant differences in genotype distributions of NOS3 rs1799983and rs2070744 polymorphisms in patients with unstable angina and healthy controls in both univariate and multivariate analyses. In patients with the NOS3 rs1799983 TT genotype, we observed a higher BMI (TT vs. GT + GG, p = 0.068), and in patients with the NOS3 rs2070744 TT genotype, we observed a higher waist circumference (TT vs. TC + CC, p = 0.023; TT vs. CC, p = 0.0053). These data suggest a lack of association between the NOS3 rs1799983andrs2070744 polymorphisms and unstable angina in our patient population. However, these polymorphisms may be associated with some obesity parameters, rs1799983 in females and rs2070744 in males.
Subject(s)
Angina, Unstable/genetics , Nitric Oxide Synthase Type III/genetics , Polymorphism, Single Nucleotide , Aged , Angina, Unstable/diagnosis , Angina, Unstable/enzymology , Case-Control Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Obesity/diagnosis , Obesity/enzymology , Obesity/genetics , Phenotype , Risk Factors , Waist Circumference/geneticsABSTRACT
Aim: This study aimed to evaluate concentration of plasma extracellular ubiquitin (UB) in coronary heart disease (CHD) patients and its correlation with the disease severity.Methods: Levels of UB and stromal cell-derived factor-1a (SDF-1a) were measured in 60 healthy controls and 67 CHD cases. Coronary atherosclerosis was assessed with Gensini scoring system. Spearman correlation was used to evaluate the correlation between UB and low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), creatine kinase-MB (CK-MB), cardiac troponin I (cTnI) or SDF-1a. The receiver-operating characteristic (ROC) curve was established to assess the predictive value of UB.Results: Plasma UB levels were significantly higher in CHD patients than in controls (p < .0001), and the levels in those with acute myocardial infarction (AMI) were higher than stable angina pectoris (SAP) and unstable angina pectoris (UAP) groups (both p < .01). UB was also positively correlated with Gensini score, CRP, CK-MB and cTnI in CHD. ROC analysis of UB showed that the area under the curve (AUC) were 0.711 (95%CI, 0.623-0.799) and 0.778 (95%CI, 0.666-0.890) for CHD and acute coronary syndrome (ACS), respectively. Plasma SDF-1a levels were elevated in CHD patients but showed no significant correlation with UB concentration or the severity of the disease.Conclusion: Plasma UB concentration was increased in CHD and the change of UB levels may reflect the progression of CHD.