Pathogenesis Of Coronary Heart Disease Research Articles

Onset of Coronary Heart Disease is Associated with HCMV Infection and Increased CD14+CD16+ Monocytes in a Population of Weifang, China

ObjectiveTo investigate the relationship between human cytomegalovirus (HCMV) infection and peripheral blood CD14+CD16+ monocytes in the pathogenesis of coronary heart disease (CHD), and to elucidate the mechanism of pathogenesis in CHD by analyzing the correlation between infection, inflammation, and CHD, to provide a basis for the prevention, evaluation, and treatment of the disease. MethodsIn total, 192 patients with CHD were divided into three groups: latent CHD, angina pectoris, and myocardial infarction. HCMV-IgM and -IgG antibodies were assessed using ELISA; CD14+CD16+ monocytes were counted using a five-type automated hematology analyzer; mononuclear cells were assessed using fluorescence-activated cell sorting; and an automatic biochemical analyzer was used to measure the levels of triglyceride, cholesterol, high- and low-density lipoprotein cholesterols, lipoprotein, hs-CRp and Hcy. ResultsThe positive rates of HCMV-IgM and -IgG were significantly higher in the CHD groups than in the control group. HCMV infection affects lipid metabolism to promote immune and inflammatory responses. ConclusionHCMV infection has a specific correlation with the occurrence and development of CHD. The expression of CD14+CD16+ mononuclear cells in the CHD group was increased accordingly and correlated with acute HCMV infection. Thus, HCMV antibody as well as peripheral blood CD14+CD16+ mononuclear cells can be used to monitor the occurrence and development of CHD.

The role of mitochondrial DNA mutations in coronary heart disease.

Coronary heart disease (CHD) is a leading cause of death worldwide. It is a multifactorial disorder resulting from harmful interactions between genetic and environmental factors. Due to the central role of mitochondria in cellular energy homeostasis, there is growing evidence supporting the role of damage to mitochondrial components such as mitochondrial DNA (mtDNA) in the pathogenesis and progression of CHD. However, the molecular mechanisms linking mtDNA and CHD remains unknown. In terms of mutations, we found that mitochondrial transfer RNA (mt-tRNA) genes are hot spots for pathogenic mutations associated with CHD. These mutations cause structural and functional changes in tRNA; specifically, failure of tRNA metabolism may impair mitochondrial protein synthesis and lead to mitochondrial dysfunction responsible for CHD. This review provides a detailed summary of the mtDNA mutations that have been reported to be associated with CHD and further discusses the possible molecular mechanisms behind the involvement of these mtDNA mutations in CHD.

Sex and Age Differences in Patients With Unstable Angina Pectoris: A Single-Center Retrospective Study

Sex and age may affect the pathogenesis of coronary heart disease, such as cardiovascular risk factors, treatment and prognosis, but this information is not well known. This was a single-center retrospective cohort study. Patients with unstable angina pectoris between January 2013 and June 2018 were included and stratified into 4 age groups (<55, 55-64, 65-74 and ≥75 years). The cardiovascular risk factors profile, treatment and in-hospital prognosis differences by sex and age were explored. This study included 5,908 patients (2,198 women). The women were older than the men (mean age 67 vs. 62 years). Approximately 2 of 3 patients had ≥3 cardiovascular risk factors. Men were more likely to be smokers, and women had a higher level of total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Hypertension, diabetes and chronic kidney disease were more frequent in women ≥ 65 years old than in similarly aged men. Men and women less than 65 years of age had more frequent family history of coronary heart disease, higher body mass index, higher fasting plasma glucose, and higher lipid levels, especially for patients <55 years of age. More women tended to receive medical therapy than men (51.6% vs. 42.8%, P < 0.01). The overall incidence of in-hospital major adverse cardiovascular events was higher in men than in women (4.1% vs. 2.6%, P < 0.05), whereas there was no sex difference in the in-hospital cardiac mortality (0.2% vs. 0.2%, P > 0.05). Women had higher cholesterol levels, and were less likely to undergo revascularization therapy than similarly aged men, and elderly women had a higher prevalence of hypertension, diabetes, and chronic kidney disease than elderly men. In-hospital major adverse cardiovascular events were lower in women than in men; however, there was no sex difference in the in-hospital cardiac mortality.

Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274

Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

Sympathetic overdrive in patients with coronary heart disease

Sympathetic overdrive (sympathetic hyperactivation) plays a key role in the pathogenesis of coronary heart disease and its adverse outcomes. An increased heart rate at rest as a manifestation of hyperactivation of the sympathetic nervous system is a factor worsening the prognosis in patients with ischemic heart disease.Beta-blockers are recognized as first-line drugs for controlling symptoms in coronary heart disease with a proven effect on prognosis. Bisoprolol is a β1-selective beta-blocker with high antianginal and prognostic modulating efficacy.

Resistin and prooxidant-antioxidant balance: Markers to discriminate acute coronary syndrome from stable angina.

BACKGROUNDResistin and oxidative stress may play a role in the pathogenesis of coronary heart disease (CHD) including acute coronary syndrome (ACS). The aim of this study was to investigate the role of serum resistin and prooxidant-antioxidant balance (PAB) in ACS occurrence in order to differentiate it from stable angina. Moreover, we aimed to determine the correlation between resistin and PAB in patients with ACS and its difference from patients with stable CHD.METHODSThis cross-sectional, descriptive study was conducted on 50 patients with ACS and 50 patients with stable CHD who underwent coronary angiography (CAG). Serum resistin level was measured using enzyme-linked immunosorbent assay (ELISA). PAB and other variables were analyzed using standard methods.RESULTSA significant increase in serum resistin and PAB was observed in patients with ACS (2.55 ± 0.13 ng/ml and 123.5 ± 5.58 HK unit, respectively) compared to patients with stable CHD (1.53 ± 0.12 ng/ml and 95.9 ± 2.7 HK unit, respectively) (P < 0.001). In addition, a significant positive correlation was seen between serum resistin and PAB in patients with ACS (r = 0.39; P = 0.005), but this correlation was not found in patients with stable CHD (r = 0.21; P = 0.140). Resistin (r = 0.52; P < 0.001) and PAB (r = 0.55; P < 0.001) were significantly associated with high-sensitivity C-reactive protein (hs-CRP) in patients with ACS, but this association was not found in patients with stable CHD (resistin: r = 0.24; P = 0.090; PAB: r = -0.02: P = 0.910).CONCLUSIONHigh serum resistin or PAB levels, and their association with the occurrence of ACS, can be used as a robust discriminating factor to differentiate ACS from stable CHD.

Low Level Antibodies Against Alpha-Tropomyosin Are Associated With Increased Risk of Coronary Heart Disease.

ObjectiveNatural autoantibodies have been implicated to play a key role in the pathogenesis of coronary heart disease (CHD) because they augment autoimmune activation. The aim of this study was to identify novel specific autoantibodies of CHD, and analyze the relationship between their levels and CHD risk indicators.Approach and ResultsFirst, clinical data and sera from CHD patients were collected. Then, one protein microarray containing 37 proteins that represent candidate autoantigens was developed. The arrays were used to profile autoantibodies in randomly selected sera from 35 samples (20 CHD patients, and 15 healthy controls). After that, microarray data were analyzed and autoantibodies for CHD were screened out. Then, ELISA detection was conducted to validate the differentiable autoantibodies using larger numbers of serum samples (131 CHD patients, and 131 healthy controls). Finally, the associations of antibodies with CHD risk indicator parameters were assessed. Inter-group comparison by microarray indicated that three CHD novel autoantibodies, including glucose-6-phosphate isomerase (G6PI), alpha-tropomyosin (TPM1), and heterogeneous nuclear ribonucleoprotein D-like (HnRNPDL), were significantly (P < 0.05) increased when compared with the healthy controls. Moreover, a significant increase of IgG autoantibodies for these three autoantigens was confirmed in CHD patients by ELISA (P < 0.0001). The correction analysis revealed a negative correlation of anti-TPM1 antibody levels and total cholesterol (P = 0.0034), and low-density lipoprotein cholesterol (P = 0.0086), respectively.ConclusionG6PI, TPM1, and HnRNPDL were CHD natural autoantigens, and serum anti-TPM1 antibody could be used as a potential marker to predict the risk for CHD patients.

MiR-202-3p Inhibits Foam Cell Formation and is Associated with Coronary Heart Disease Risk in a Chinese Population

A previous study and a gene-annotation enrichment analysis for potential targets of the microRNA miR-202-3p both suggest that this microRNA might be implicated in cardiovascular and metabolic diseases. In the present study, the role of miR-202-3p in the pathogenesis of coronary heart disease (CHD) was explored. We conduct a case-control study to detect the expression levels of miR-202-3p in peripheral blood cells and found that miR-202-3p expression was significantly higher in CHD cases than in controls (P < 0.001). miR-202-3p levels were negatively correlated with platelet distribution width (r = -0.348, P = 0.002) and mean platelet volume (r = -0.29, P = 0.01). Further functional analyses suggested that stimulation with oxidized low-density lipoprotein (ox-LDL) induced miR-202-3p expression, and that this microRNA suppressed the formation of ox-LDL-induced macrophage foam cells derived from THP-1 cells in a feedback manner. In addition, miR-202-3p overexpression modulated the expression of several key genes involved in foam cell formation, including that of ABCG4, NCEH1I, and SCARB2. In summary, miR-202-3p was associated with CHD, exerting a protective role against CHD by feedback suppression of ox-LDL-induced macrophage foam cell formation.

Concentration omentin-1 in the serum of patients with coronary heart disease

Background. Omentin-1 (QM-1) — one of the most important anti-inflammatory adipocytokines produced by adipose tissue. It is known that its concentration is reduced in obese patients. However, the role of OM-\ in the pathogenesis of coronary heart disease (CHD), including acute coronary syndrome (ACS), is not fully determined.The objective of the study — to assess the level of OM-1 in blood serum of patients with ACS without ST-segment elevation (ACSWEST) who underwent percutaneous coronary intervention (PCI) and patients with stable CHD.Design and methods. Examined 104 patients with ACSWEST undergoing PCI. Comparison groups consisted of 38 patients without CHD according negative results of stress-echocardiography or coronary angiography, as well as 80 patients with stable CHD. All patients were evaluated anthropometric indicators: height, weight, waist circumference (WC), body mass index (BMI). Serum concentrations of OM-I were determined by enzyme immunoassay (DRG,USA), serum lipid profile was determined by enzymatic method.Results. In patients with ACSWEST who underwent PCI, the concentration of OM-I in the blood is lower than in those examined without atherosclerotic lesions of the coronary arteries [7.53 (5.00-10.55) ng/ml and 12.56 (7.84-15.34) ng/ml, respectively; p &lt; 0.001). The concentration of OM-1 in the blood in patients with ACSWEST and a stable CHD did not differ (p &gt; 0.05). In patients with ACSWEST, the concentration of OM-1 blood with multivascular lesions of the coronary arteries is lower than with 1-2 vascular lesions [7.30 (3.91- 8.17) ng/ml and 9.44 (6.54-9.93) ng/ml, respectively; p &lt; 0.001. Similar patterns were established in patients with a stable CHD (p &lt; 0.001).The concentration of OM-1 inthe blood in women with ACSWEST, with stable CHD and in those examined without CHD was higher than in men of the corresponding groups (p &lt; 0.001).In patients with ACSWEST and with a stable CHD with overweight and obesity (WHO, 1999), the concentration of OM-1 inblood serum is lower than in patients with CHD and normal BMI (p &lt; 0.001). In patients with ACSWEST and AO, the level of OM-1 inthe blood is lower than in patients with ACSWEST without AO, both in men and women (p &lt; 0.001). When conducting a regression analysis, it was found that the concentration of OM-1 inthe blood of patients with ACSWEST is determined by BMI (b = -0.30, beta = -0.23, p = 0.002) and patient gender (b = 2.21, beta = 0.16, p = 0.029); in patients with a stable CHD — BMI (b = -0.38, beta = -0.27, p = 0.029).Conclusion. For patients with CHD, both with ACSWEST and with stable CHD, a low level of OM-1 in the blood is characteristic. The lowest OM-1 values were found in patients with multivascular coronary artery disease and obesity. The gender characteristics of the concentration of OM-1 in serum were established: the concentration of OM-1 in serum in women is higher than in men. A decrease in the concentration of OM-1 in the blood in patients with ACSWEST and with stable CHD is associated with BMI, the patient’s gender, and the severity of coronary atherosclerosis.

Inflammation and Coronary Heart Disease Risk in Patients with Depression in China Mainland: A Cross-Sectional Study.

ObjectiveThe risk of coronary heart disease (CHD) in patients with major depressive disorder (MDD) is higher than that in the general population. However, the mechanisms underlying the increased CHD risk in patients with MDD remain unclear. Inflammation plays an important role in the pathogenesis of MDD and CHD. Therefore, we explored the relationship between inflammatory biomarkers and CHD risk in patients with MDD.MethodsWe included 454 patients with acute MDD and 458 controls that matched the sample in age and gender. A readily available complete blood count was used to reflect inflammation, and the risk of CHD was assessed using the Framingham risk score.ResultsThe results showed that patients with MDD showed low-grade inflammation with an elevated platelet (p<0.001) and monocyte count (p<0.001), high platelet/lymphocyte (p=0.003) and monocyte/lymphocyte ratios (p<0.001), and a raised systemic immune-inflammation index (p=0.002). In addition, monocyte count was the only factor significantly associated with CHD risk in patients with MDD (B=7.521, 95% CI: 3.409–11.633, t=3.594, p<0.001).ConclusionCollectively, the results of this study support the hypothesis that MDD is systemic inflammation, and suggest that monocyte count predicts the risk of CHD in patients with MDD.

Regulatory Factor X1 Downregulation Contributes to Monocyte Chemoattractant Protein-1 Overexpression in CD14+ Monocytes via Epigenetic Mechanisms in Coronary Heart Disease.

Monocyte chemoattractant protein 1 (MCP1) affects the chemotaxis of monocytes and is a key chemokine closely related to the development of atherosclerosis (AS). Compared with healthy controls, coronary heart disease (CAD) patients show significantly upregulated plasma concentrations and mRNA expression of MCP1 in CD14+ monocytes. However, the specific regulatory mechanism of MCP1 overexpression in AS is still unclear. Our previous research indicated that there was no significant difference in the H3K4 and H3K27 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD versus non-CAD patients, but the H3 and H4 acetylation of the MCP1 promoter was increased in CD14+ monocytes from CAD patients. We further found that the H3K9 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD patients was decreased, but the DNA methylation levels did not differ markedly from those in non-CAD patients. Our previous work showed that the level of regulatory factor X1 (RFX1) was markedly reduced in CD14+ monocytes from CAD patients and played an important role in the progression of AS by regulating epigenetic modification. In this study, we investigated whether RFX1 and epigenetic modifications mediated by RFX1 contribute to the overexpression of MCP1 in activated monocytes in CAD patients. We found that the enrichment of RFX1, histone deacetylase 1 (HDAC1), and suppressor of variegation 3–9 homolog 1 (SUV39H1) in the MCP1 gene promoter region were decreased in CD14+ monocytes from CAD patients and in healthy CD14+ monocytes treated with low-density lipoprotein (LDL). Chromatin immunoprecipitation (ChIP) assays identified MCP1 as a target gene of RFX1. Overexpression of RFX1 increased the recruitments of HDAC1 and SUV39H1 and inhibited the expression of MCP1 in CD14+ monocytes. In contrast, knockdown of RFX1 in CD14+ monocytes reduced the recruitments of HDAC1 and SUV39H1 in the MCP1 promoter region, thereby facilitating H3 and H4 acetylation and H3K9 tri-methylation in this region. In conclusion, our results indicated that RFX1 expression deficiency in CD14+ monocytes from CAD patients contributed to MCP1 overexpression via a deficiency of recruitments of HDAC1 and SUV39H1 in the MCP1 promoter, which highlighted the vital role of RFX1 in the pathogenesis of CAD.

P6431Association of circulating miR-765, miR-93-5p and miR-433-3p with obstructive coronary heart disease evaluated by cardiac computed tomography

Abstract Background Although advances in diagnosis, treatment and prognosis, coronary heart disease (CHD) is still the most prevalent cause of mortality and morbidity worldwide. Thus, there is still the need to identify both novel diagnostic and prognostic biomarkers to improve the clinical decision-making and help to stratify patients for early preventive treatment. Epigenetic-sensitive mechanisms may be related both to pathogenesis and prognosis of CHD. Among the epigenetic hallmarks, microRNAs (miRNAs), acting as flexible modulators of gene expression, could represent attractive candidate biomarkers useful in clinical practice. Purpose We prospectively investigated the expression pattern of circulating miRNAs in patients undergoing Cardiac Computed Tomography (CCT) for suspected CHD (n=95) with the aim to integrate molecular findings with morphological and clinical parameters derived by CCT. Methods CCT was performed with a third-generation dual source multidetector computed tomography scanner. Peripheral venous blood samples were collected into EDTA after a 12 h fasting in the same day of CCT, before imaging execution and the levels of 42 selected plasmatic miRNAs were analyzed by qRT-PCR. Results Let-7c-5p, miR-765, miR-483-5p, miR-31-5p and miR-206 were upregulated in CHD patients (n=66) vs healthy subjects HS (n=29) as well as let-7c-5p, miR-765, miR- 483-5p showed higher expression in obstructive CHD (n=36) compared to no obstructive CHD patients (n=66). In addition, miR-93-5p and miR-433-3p showed an upregulation in patients with critical coronary stenosis. Multivariate regression analysis demonstrated that miR-765, miR-31-5p and miR-206 were independently associated with CHD also in combination with Framingham risk score. Relevantly, miR-765, miR-93-5p and miR-433-3p were obstructive CHD predictors. ROC curve analysis also revealed a good performance for miR-765, miR-93-5p and miR-433-3p on predicting CHD severity. Circulating microRNA expression Conclusions Our study represents a combined epigenetic/imaging approach useful to support the diagnosis and prediction of CHD. Acknowledgement/Funding Italian Ministry of Health grants: “Giovani Ricercatori 2011-12” (project code GR-2011-02349436) and “Ricerca Corrente 2018”

A male-specific association between AGTR1 hypermethylation and coronary heart disease.

The AGTR1 gene encodes angiotensin II receptor type 1, which is involved in cardiovascular diseases such as coronary heart disease (CHD). In the current study, we analyzed AGTR1 promoter methylation level in a Han Chinese population by SYBR green-based quantitative methylation-specific PCR (qMSP). We collected blood samples from 761 CHD patients and 398 non-CHD controls at the Ningbo First Hospital. A data mining analysis was also performed to explore the association between AGTR1 methylation and AGTR1 gene expression, using datasets from the cBioPortal for Cancer Genomics and the Gene Expression Omnibus (GEO) database. Our results showed a significantly higher percentage of methylated reference (PMR) of AGTR1 in male CHD patients compared with male non-CHD controls (median PMR: 2.12% vs. 0.59%, p = 0.037). The data mining analysis showed that AGTR1 expression was significantly increased in human hepatoma HepG2 cells treated with the demethylation agent 5-aza-2’-deoxycytidine (fold = 3.12, p = 0.009). Further data mining analysis using the cholangiocarcinoma (TCGA, PanCancer Atlas) data indicated an inverse association between AGTR1 methylation and AGTR1 expression (r = -0.595, p = 1.29E-04). Overall, our results suggest that AGTR1 methylation is involved in the regulation of AGTR1 gene expression and that AGTR1 hypermethylation is associated with CHD in males. These findings may provide new clues about the pathogenesis of CHD.

Cecal Gut Microbiota and Metabolites Might Contribute to the Severity of Acute Myocardial Ischemia by Impacting the Intestinal Permeability, Oxidative Stress, and Energy Metabolism.

Emerging evidence highlights the role of gut microbiota in regulating the pathogenesis of coronary heart disease. Here, we performed 16S rRNA gene sequencing and UPLC-Q-TOF/MS-based metabolomics to investigate the gut microbiome and metabolomes of cecal contents in the isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rats. As expected, considerable gut microbiota alterations were observed in the AMI rats compared with the control rats, paralleling with intestinal inflammation and apoptosis. At phylum level, the abundance of Firmicutes was significantly decreased, whereas the abundance of Bacteroidetes and Spirochaetae was strikingly enriched in the AMI group. At genus level, the significant alteration of genera Treponema 2, Rikenellaceae RC9 gut group, Prevotellaceae UCG-003, and Bacteroides may contribute to the pathogenesis of AMI. These altered microbiota might influence the intestinal permeability and subsequently impair intestinal barrier and stimulate gut inflammation. Consistently, significantly metabolic differences of cecal contents between the AMI and control groups were revealed, and threonic acid, L-urobilin and L-urobilinogen were considered the most associated cecal metabolites with AMI. These strikingly altered metabolites were mainly related to energy metabolism and oxidative stress which could lead to apoptosis and further affect gut barrier. Ultimately, we revealed the potential link of these altered gut microbiota/metabolomes and intestinal inflammatory factors and apoptotic proteins and further confirmed their intimate connections with intestinal inflammation and gut barrier. Our findings depict uncovered potential relationship among the gut microbiome, cecal metabolomes and AMI.

Functional association of a CD40 gene single-nucleotide polymorphism with the pathogenesis of coronary heart disease.

Endothelial dysfunction is a major contributor to the pathogenesis of atherosclerosis. CD40-CD40 ligand interactions confer a pro-inflammatory phenotype to endothelial cells (ECs). Recently, a thymine to cytosine transition (-1T>C) in the Kozak sequence of the CD40 gene (rs1883832) has been associated with coronary heart disease (CHD) in an Asian population. As there are no reports yet regarding its role in other ethnic groups, this study determines if the -1T>C single-nucleotide polymorphism (SNP) could be a risk factor for CHD in Caucasians by performing an association study and elucidates its functional consequence in cultured ECs. Molecular and biochemical techniques, cell adhesion assays were used for genotype-stratified human EC characterization. SNP distribution in Caucasians was examined in a hospital-based case-control CHD study and serum levels of soluble CD40 (sCD40) were quantified by ELISA. The SNP in the CD40 gene affected baseline CD40 protein abundance on ECs. There was a genotype-dependent difference in CD40-mediated expression of pro-inflammatory genes. Monocyte adhesion was highest on the surface of cells homozygous for the C allele. Homozygosity for the C allele was associated with significant 2.32-fold higher odds of developing CHD as compared to TT genotype carriers. sCD40 plasma levels were genotype-dependently elevated in CHD patients, indicating a possible prognostic value. The C allele of the CD40 SNP provokes a pro-inflammatory EC phenotype, compensated by an enhanced CD40 shedding to neutralize excess CD40 ligand. Homozygosity for the C allele is the cause for a genetic susceptibility to atherosclerosis and its sequelae.

NLRP3 inflammasome expression in peripheral blood monocytes of coronary heart disease patients and its modulation by rosuvastatin

Nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in a series of physiological and pathological processes. However, its correlation in coronary heart disease (CHD) still remains to be elucidated. The present study aimed to determine the expression of NLRP3 inflammasome in peripheral blood monocytes (PBMCs) of stable angina pectoris (SAP) and acute myocardial infarction (AMI) patients. In addition, the effect of rosuvastatin on their activities was analyzed in vitro. A total of 60 participants with SAP (n=20), AMI (n=20) and non-CHD controls (n=20) were enrolled. Fluorescence-activated cell sorting, real-time PCR, western blotting and enzyme-linked immunosorbent assay were performed to reveal the role of NLRP3 inflammasome. NLRP3 inflammasome was expressed in the PBMCs, and revealed an increased expression along the downstream interleukin (IL)-1β and IL-18 in both SAP and AMI groups, compared to the control group. Moreover, there was a more marked increase in the expression of these indicators in AMI patients when compared to SAP patients. Interference with rosuvastatin in vitro revealed that the expression of NLRP3 inflammasome and its downstream cytokines were significantly downregulated in both SAP and AMI groups in a time-dependent manner. The activation of NLRP3 inflammasome may be involved in the development of CHD, and rosuvastatin could attenuate the inflammatory process of atherosclerosis by downregulating NLRP3 expression and its downstream mediators. These findings indicated a potential role of NLRP3 in the pathogenesis and management of CHD, and also provided new insights into the mechanistic framework of rosuvastatin activity.

The effect of tumor necrosis factor alpha (-308G/a) and interferon gamma (+874T/a) polymorphisms on susceptibility to coronary heart disease

Background: Coronary heart disease (CHD) is a chronic inflammatory disease, which is still regarded as a major cause of morbidity and mortality worldwide. Several studies have suggested that polymorphisms in cytokine genes are associated with the pathogenesis of CHD. The genotype distribution of Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) genes polymorphisms have been shown to be different in various ethnic populations. This study was aimed to investigate the association of TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms with risk of CHD in an Iranian population.Methods: A total of 187 unrelated subjects comprised 96 CHD patients and 91 healthy controls were enrolled in this cross-sectional study. The TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms were genotyped using amplification refractory mutation system-PCR (ARMS-PCR). The chi-square and logistic regression tests were used to calculate the odds ratios (ORs) as a measure of differences in genotype frequencies.Results: A significant differences in the allelic and genotypic distribution of TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms was found between CHD patients and healthy controls (P = 0.017, P = 0.011, P = 0.006 and P = 0.002, respectively). Logistic regression analyses were also revealed statistically significant risk for CHD with respect to TNF-α-308 A and IFN-γ + 874 T carriers either in crude or after adjustment for potential confounders (P = 0.003 and P = 0.006, respectively).Conclusion: This study provides strong evidence supporting the association of TNF-α-308G/A and IFN-γ + 874T/A polymorphisms with the increased risk of CHD. Therefore, these two cytokine polymorphisms may play a role in predisposition to coronary heart disease.

Association between reduced brain-derived neurotrophic factor concentration & coronary heart disease.

Background & objectives:Brain-derived neurotrophic factor (BDNF) facilitates neuronal survival, differentiation and synaptic connectivity and affects neurotransmission throughout the brain. However, it has also a modulatory role in energy homeostasis, obesity and cardiovascular function. Obesity, high body mass index (BMI) and dyslipidaemia, among other factors, contribute to coronary heart disease (CHD) development. The exact role of BDNF in development of CHD is not well defined. This study was aimed to evaluate if plasma BDNF concentration was associated with CHD in ethnically homogeneous groups of patients and to correlate plasma BDNF levels with known risk factors for CHD.Methods:Plasma BDNF concentration, BDNF Val66Met polymorphism and other biological and anthropological risk factors for CHD were determined in 208 patients with CHD and 156 healthy controls.Results:Plasma BDNF concentration was significantly (P<0.01) reduced in patients with CHD compared to controls, and it was not influenced by gender, age, smoking or BDNF Val66Met polymorphism. It was considerably correlated with cholesterol (P=0.004), low-density lipoprotein (P=0.006), and diastolic blood pressure (P=0.018) in patients with CHD and with platelet number (P=0.003) in healthy controls.Interpretation & conclusions:The results revealed lower plasma BDNF concentration in patients with CHD, suggesting that decreased plasma BDNF concentration might be associated with CHD pathogenesis. Longitudinal studies with a large sample need to be conducted to confirm these findings.

Elevated methylation of cyclin dependent kinase inhibitor 2B contributes to the risk of coronary heart disease in women.

Cyclin dependent kinase inhibitor 2B (CDKN2B) encodes a cyclin-dependent kinase inhibitor that may enhance the formation of atherosclerotic plaques. The aim of the present study was to investigate the contribution of CDKN2B promoter methylation on the risk of coronary heart disease (CHD). The present results indicated a significant association between increased CDKN2B methylation and the risk of CHD (adjusted P=0.043). A breakdown analysis according to sex demonstrated that CDKN2B methylation was significantly associated with the risk of CHD in women (adjusted P=0.010), but not in men. A further breakdown analysis by age indicated a significant association of CHD in the women >60 years (P=0.024). Luciferase reporter gene assay results indicated that the CDKN2B promoter fragment significantly enhanced luciferase activity (P<0.001). In addition, CDKN2B transcription was significantly enhanced following treatment with 5-aza-2′-deoxycytidine methylation inhibitor in human aortic endothelial cells (HAEC) and human primary coronary artery smooth muscle cells (HPCASMC; P<0.05 and P<0.01), but not in 293 cells. Notably, estrogen treatment reduced CDKN2B methylation of several CpGs and significantly increased CDKN2B gene expression levels in HAEC, HPCASMC and 293 cells (P<0.05 and P<0.01). Additionally, treatment of HAEC and HPCASMC with simvastatin and γ-carboxy-L-glutamic acid reduced CDKN2B promoter methylation and increased CDKN2B transcription concomitantly. The present study suggests that CDKN2B promoter methylation may be associated with sex dimorphism in the pathogenesis of CHD.

Circ-SATB2 upregulates STIM1 expression and regulates vascular smooth muscle cell proliferation and differentiation through miR-939

The prevention and treatment of coronary heart disease (CHD) is a difficult problem to be solved. More and more studies have found that circular RNAs (circRNAs) may play important roles in the development of CHD. Here detection of vascular smooth muscle cells (VSMCs) showed that circ-SATB2 and STIM1 were up-regulated in proliferative VSMCs, while miR-939 were down-regulated. Circ-SATB2 and miR-939 did not affect the expression of each other, but circ-SATB2 could promote while miR-939 inhibited the expression of STIM1 (a target gene of miR-939). Circ-SATB2 overexpression could inhibit the expression of SM22-alpha (SM22α, a marker of contractile VSMCs), while the expression of SM22α was promoted by miR-939. STIM1 could promote cell proliferation and migration, and circ-SATB2 had similar effects, but its linear sequence had no such functions. MiR-939 had the opposite effects, could promote cell apoptosis and inhibit cell proliferation and migration, and siRNAs targeting circ-SATB2 had similar effects. When co-transfected with circ-SATB2 over-expression vector and miR-939 mimics or STIM1 siRNAs, the changes of cell proliferation, apoptosis and migration were not significant. Therefore, circ-SATB2 can regulate VSMC phenotypic differentiation, proliferation, apoptosis and migration by promoting the expression of STIM1. This discovery will provide a theoretical reference for exploring the role of circRNA in VSMCs and the pathogenesis of CHD.