Histone Deacetylase 1 Depletion Alleviates Coronary Heart Disease Via the MicroRNA-182-Mediated Transforming Growth Factor ß/Smad Signaling Pathway.

ABSTRACT: Histone deacetylase (HDAC) determines the acetylation status of histones, thereby regulating gene expression. HDAC inhibitors have been demonstrated to suppress cardiomyocyte growth in vitro and in vivo. We assessed here whether HDAC1 exerts an aggravating effect on coronary heart disease (CHD). Epigenetic probe array revealed that HDAC1 was overexpressed in patients with CHD. HDAC1 was then downregulated in rat cardiomyocytes, and microRNA microarray analysis was performed to detect downstream targets of HDAC1, followed by chromatin immunoprecipitation validation. HDAC1 inhibited miR-182 expression through deacetylation. miR-182 was poorly expressed in patients with CHD. Using enzyme-linked immunosorbent assay, Reverse transcription-quantitative PCR, hematoxylin-eosin staining, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assay, and immunohistochemistry, we observed that HDAC1 downregulation promoted cardiac function, restored lipid levels, reduced myocardial injury markers and inflammatory factors, and alleviated myocardial tissue damage and apoptosis in CHD rats. By contrast, miR-182 downregulation exacerbated injury in rats in the presence of HDAC1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes of miR-182 were mainly enriched in the transforming growth factor (TGF)-ß/Smad pathway. Western blot also validated that HDAC1/miR-182 modulated the TGF-ß/Smad pathway activity. Our results demonstrated that HDAC1 repressed miR-182 and activated the TGF-ß/Smad pathway to promote CHD.

FTZ attenuates liver steatosis and fibrosis in the minipigs with type 2 diabetes by regulating the AMPK signaling pathway.

Fufang Zhenzhu Tiaozhi formula (FTZ), a preparation of Chinese herbal medicine, has various pharmacological properties, such as hypoglycemic, hypolipidemic, anticoagulant, and anti-inflammatory activities. Hepatocyte apoptosis is a marker of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. Given the multiple effects of FTZ, we investigated whether FTZ can be a therapeutic agent for NASH and its mechanism. In the present study, we observed that FTZ treatment had an obviously favorable influence on hepatic steatosis and fibrosis in the histopathologic features of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) with NASH minipigs. In addition, immunohistochemical analysis showed increased expression of the fibrotic marker α-smooth muscle actin (α-SMA), and a TUNEL assay revealed increased apoptotic positive hepatic cells in the liver tissues of the model group. Furthermore, FTZ administration reduced the increased expression of α-SMA, and FTZ inhibited apoptosis by affecting Bcl-2/Bax and cleaved caspase-3 expression. Mechanistically, our data suggested that FTZ treatment attenuated hepatic steatosis and fibrosis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. In vitro studies showed that FTZ also attenuated intracellular lipid accumulation in HepG2 cells exposed to palmitic acid (PA) and oleic acid (OA). FTZ upregulated the expression levels of P-AMPK and BCL-2 and downregulated BAX. The changes induced by FTZ were reversed by Compound C, an inhibitor of AMPK. In conclusion, FTZ attenuated NASH by ameliorating steatosis and hepatocyte apoptosis, which is attributable to the regulation of the AMPK pathway.

Association of GSTP1 Ile105Val polymorphism with the risk of coronary heart disease: An updated meta-analysis.

BACKGROUND: Numerous case-control studies have investigated the association between GSTP1 Ile105Val polymorphism and CHD risk, but the results from published studies were inconclusive. The present meta-analysis was performed to derive a more precise estimation. METHODS: PubMed, EMBASE, and Web of Science database searches were conducted to retrieve relevant articles. RESULTS: Ultimately, 5,451 CHD cases and 5,561 controls from 15 studies were included. Pooled analysis did not yield any statistically significant association between GSTP1 Ile105Val polymorphism and CHD risk for the overall population (Val vs. Ile: OR, 1.05; 95% CI, 0.93 to 1.18; Val/Val vs. Ile/Ile: OR, 1.09; 95% CI, 0.83 to 1.42; Val/Ile vs. Ile/Ile: OR, 1.09; 95% CI, 0.93 to 1.28; Val/Val vs. Val/Ile+Ile/Ile: OR, 1.04; 95% CI, 0.83 to 1.30; Val/Val+Val/Ile vs. Ile/Ile: OR, 1.14; 95% CI, 0.97 to 1.33). Subgroup analyses and sensitivity analyses indicated that GSTP1 Ile105Val polymorphism was still not associated with an increased risk of CHD. After excluding studies detected by Galbraith plots as major sources of heterogeneity, these relationships were still not significant. CONCLUSIONS: The overall results did not reveal a major role of the GSTP1 Ile105Val polymorphism in modulating CHD risk. Well-designed studies with large sample sizes are needed to validate our findings and explore the possible gene-gene or gene-environment interactions.

Significances of viable synergistic autophagy-associated cathepsin B and cathepsin D (CTSB/CTSD) as potential biomarkers for sudden cardiac death.

BACKGROUND: The Cathepsins family, including cathepsin B and cathepsin D, potentially affects the entire processes involved in atherosclerosis. Although coronary heart disease (CHD) has been widely studied as the basis of Sudden Cardiac Death (SCD), the relationship between CHD and CTSB/D remains unclear. METHODS: We screened for differentially expressed proteins (DEPs) associated with autophagy by limma package in R. For the genes corresponding to the DEPs after screening, we used various databases to carry out functional enrichment of related DEGs to explore their possible influence on a specific aspect of the disease. Functional enrichment analysis of DEGs was performed by DAVID, Metascape and GSEA. STRING and Cytoscape were obtained the hub genes, the analysis of interaction networks through the GENMANIA and Networkanalyst. Western Blot was used to validate the protein expression level of target genes. TF and miRNA prediction were performed using Networkanalyst and visualized using Cytoscape. RESULTS: The expression levels of members of the cathepsin family were up regulated in CHD tissues compared with the control. GO and KEGG revealed that cathepsin was markedly enriched in endopeptidase activities, immune responses, lysosome pathways, et al. The correlation analysis showed that in patients with CHD, the CTSB/CTSD expression were negatively correlated with ATG4D and BNIP3, but positively with BCL2L1, CAPNS1, and TP53. In the TF-mRNA-miRNA network, has-miR-24-3p and has-miR-128-3p had higher degrees, CTSB/CTSD could be targeted by them. CONCLUSIONS: Our findings elucidated the expression and regulatory role of cathepsins in coronary heart disease induced SCD and might further explore the potential mechanisms of autophagy in CHD.

Kounis Syndrome­not a Single-organ Arterial Disorder but a Multisystem and Multidisciplinary Disease

Coronary symptoms associated with conditions related to mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, further inducing allergic, hypersensitivity, anaphylactic, or anaphylactic insults, are currently referred to as the Kounis syndrome. Kounis syndrome is caused by inflammatory mediators released during allergic insults, post-inflammatory cell activation, and interactions via multidirectional stimuli. A platelet subset of 20% with high- and low-affinity IgE surface receptors is also involved in this process. Kounis syndrome is not just a single-organ but also a complex multisystem and multi-organ arterial clinical condition; it affects the coronary, mesenteric, and cerebral arteries and is accompanied by allergy­hypersensitivity­anaphylaxis involving the skin, respiratory, and vascular systems in the context of anesthesia, surgery, radiology, oncology, or even dental and psychiatric medicine; further, it has significantly influences both morbidity and mortality. Kounis syndrome might be caused by numerous and continuously increasing causes, with broad clinical symptoms and signs, via multi-organ arterial system involvement, in patients of any age, thereby demonstrating predominant anaphylactic features in terms of a wide spectrum of mast cell-association disorders. Cardiac symptoms, such as chest pain, coronary vasospasm, angina pectoris, myocardial infarction, stent thrombosis, acute cardiac failure, and sudden cardiac death associated with subclinical, clinical, acute, or chronic allergic reactions, constitute the clinical manifestations of this syndrome. Since its first description, a common pathway between allergic and non-allergic coronary events has been demonstrated. The hypothesis is based on the existence of a much higher degree of mast cell degranulation at plaque erosion or rupture sites compared with at the adjacent areas or even more distant segments in post-acute myocardial infarction of non-allergic etiology. Although mast cell activation, differentiation, and mediator release takes days or weeks, the mast cell degranulation may occur just before any acute coronary event, further resulting in coronary artery vasoconstriction and atheromatous plaque rupture. It seems that medications and natural molecules stabilizing the mast cell membrane as well as monoclonal antibodies protecting the mast cell surface can emerge as novel therapeutic modalities for acute coronary and cerebrovascular event prevention.

Matrix Metalloproteinase 9 as a Predictor of Coronary Atherosclerotic Plaque Instability in Stable Coronary Heart Disease Patients with Elevated Lipoprotein(a) Levels.

We sought to investigate whether levels of matrix metalloproteinases (MMPs) and their inhibitors predict coronary atherosclerotic plaque instability, as assessed by intravascular ultrasound (IVUS) virtual histology during coronary angiography. Blood samples were collected before angiography in 32 subjects (mean age 56 ± 8 years) with stable coronary heart disease (CHD) and elevated lipoprotein(a) (Lp(a), 94 ± 35 mg/dL). Levels of high-sensitivity C-reactive protein (hsCRP), apolipoprotein B100 (apoB100), MMP-7, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 were determined using commercially available enzyme-linked immunosorbent assay kits. Results. The morphology of a total of sixty coronary lesions was assessed by virtual histology IVUS imaging. Eleven (18%) plaques in nine (28%) patients were classified as plaques with an unstable phenotype or a thin-cap fibroatheroma. Age, low-density lipoprotein cholesterol, apoB100, MMP-7, and MMP-9 levels were positively associated with necrotic core volume. Conversely, there was a negative relationship between MMP-7 and -9 levels and fibrous and fibro-fatty tissue volume. Multivariate regression analysis revealed that MMP-9 is a strong independent predictor of atherosclerotic plaque instability in stable CHD patients. In stable CHD patients with elevated Lp(a), MMP-9 levels are positively associated with the size of the necrotic core of coronary atherosclerotic plaques.

Variability in gelatinase expression in the walls of vessels used as aortocoronary conduits may impact long-term graft patency.

BACKGROUND: An imbalance between the activity of matrix metalloproteinases (MMPs), particularly gelatinases, and tissue inhibitors of metalloproteinases (TIMPs) is considered as one of the mechanisms leading to aortocoronary graft failure. AIM: We aimed to assess the variability in gelatinase expression in the walls of aortocoronary conduits and to evaluate its impact on coronary artery bypass grafting (CABG) outcomes. METHODS: The study included 101 consecutive patients (61 men and 40 women) who underwent CABG. An immunohisto-chemical analysis of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression was performed on the cross-sections of the internal thoracic artery (ITA), radial artery (RA), and saphenous vein (SV). The histological findings were compared between patients with SV graft disease (SVGD[+] group) and those without occlusions in the SV (SVGD[-] group). RESULTS: The median MMP and TIMP expression was the weakest in the ITA wall. MMP expression was comparable between the RA and SV cross-sections, whereas TIMP expression was stronger in the RA than in the SV wall (p < 0.05). In most SV segments, but not in the arteries, immunostaining intensity for MMP was comparable to or stronger than for TIMPs. In the veins harvested from the SVGD(+) group, MMP-2 and MMP-9 tissue expression was more pronounced than in the SVGD(-) group. TIMP levels were comparable between groups. CONCLUSIONS: Imbalance in the metalloproteinase-to-inhibitor tissue expression in the vessel wall might predispose to graft failure. A stronger expression of TIMPs than MMPs in the arterial grafts might explain favourable long-term outcomes.

PCSK9 inhibition 2018: riding a new wave of coronary prevention.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates the low-density lipoprotein cholesterol (LDL-c) receptor and thus circulating LDL-c levels. With overwhelming evidence now supporting the reduction in LDL-c to lower the risk of cardiovascular disease, PCSK9 inhibitors represent an important therapeutic target, particularly in high-risk populations. Here, we summarise and update the science of PCSK9, including its discovery and the development of various inhibitors, including the now approved monoclonal antibodies. In addition, we summarise the clinical applications of PCSK9 inhibitors in a range of patient populations, as well as the major randomised controlled trials investigating their use in coronary prevention.

Unexpectedly higher diazoxon hydrolysis by serum paraoxonase-1 in coronary heart disease.

OBJECTIVES: Low serum PON1 activities (paraoxon, phenyl-acetate or lactone substrates) are associated with coronary heart disease (CHD). We investigated the rate of diazoxon hydrolysis by PON1 in a population with CHD. DESIGN & METHODS: Case- control study of 410 subjects with CHD and 274 controls. PON1 activity towards paraoxon and diazoxon, PON1 serum concentration and the PON1-55 and 192 polymorphisms were determined. RESULTS: There were no differences in the distribution of the PON1-55 or PON1-192 genotypes between the CHD and controls, however, PON1 activity towards diazoxon (DIAZ) was significantly (+160%) higher in CHD. In the control population, DIAZ was significantly different between the PON1-192 genotypes in the order QQ > QR > RR (P < .001). However, in CHD the order was QQ > QR = RR. In CHD DIAZ was significantly higher in all the PON1-192 and 55 genotypes compared to controls. In both populations DIAZ was significantly different between the PON1-55 genotypes in the order LL > LM > MM (P < .001). CONCLUSION: If this result can be replicated in other studies and/or with other PON1 substrates, there may be major diagnostic and mechanistic implications for the relationship of PON1 and CHD.

The association between an endothelial nitric oxide synthase gene polymorphism and coronary heart disease in young people and the underlying mechanism.

With the development of molecular biological technology, the association between genes and diseases has drawn increasing attention of researchers; the endothelial nitric oxide synthase (eNOS) gene has been reported to be a candidate gene for cardiovascular disease (CHD). The present study aimed to investigate the association between a polymorphism of eNOS and the risk of CHD in young people (≤40 years old), in addition to the underlying mechanism. A total of 234 cases of CHD in young individuals were collected as the CHD group and 228 cases of healthy individuals as the control group. Peripheral blood was collected and the genotype of the eNOS G894T polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism, the gene frequency was calculated and the distributions of genotype and allele frequency between the two groups were compared. Bioinformatics tools were employed to analyze the differences in the local protein structures of the eNOS G894T polymorphism and the biological mechanism was preliminary discussed. The results demonstrated that there were significant differences in the distribution of genotype frequency and allele frequency of the eNOS G894T gene polymorphism between the CHD group and control group (P<0.05). The risk of CHD in GT and TT genotypes were higher compared with the GG genotype (P<0.05). The G894T polymorphism led to Glu298Asp mutation of encoded protein, which is within the active site of eNOS, and partial structures of the protein were converted from random coil to α­helix. In conclusion, the eNOS G894T gene polymorphism was associated with the occurrence and development of CHD in young people. The potential mechanism is that the G894T polymorphism leads to altered protein structure, which affects the function of eNOS in generating nitric oxide and cardiovascular diastole. The results of the present study suggested a potential target gene for the prevention and treatment of CHD in young people (≤40 years old).

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling.

BACKGROUND: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. METHODS: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). RESULTS: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10-26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10-5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01). CONCLUSIONS: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

Effects of Dual-Dose Clopidogrel, Clopidogrel Combined with Tongxinluo Capsule, and Ticagrelor on Patients with Coronary Heart Disease and CYP2C19*2 Gene Mutation After Percutaneous Coronary Interventions (PCI).

BACKGROUND In recent years, genetic factors have attracted research interest as important predisposing factors for cardiovascular susceptibility. This study aimed to investigate the influences of dual-dose clopidogrel, clopidogrel combined with tongxinluo, and ticagrelor on the platelet activity and MACE events of patients with CYP2C19*2 gene function deficiency and poor clopidogrel response after PCI. MATERIAL AND METHODS We selected 458 patients with coronary heart disease undergoing PCI, and the genotype of CYP2C19*2 was detected by TaqMan real-time PCR. We finally enrolled 212 patients and divided them into 4 groups: a standard anti-platelet group of 46 patients, a clopidogrel double-dose group of 50 cases, a clopidogrel combined with tongxinluo group of 59 cases, and a ticagrelor group of 57. The platelet inhibition rate was detected by TEG. We analyzed and compared differences in platelet activity and the occurrence of MACE events in these 4 groups at different follow-up times. RESULTS The results showed that inhibition of platelet aggregation was better in the double-dose clopidogrel group, the clopidogrel combined with tongxinluo group, and the ticagrelor group than in the regular-dose clopidogrel group, and ticagrelor was the best. We also found that the total incidence of MACE was much lower in the double-dose clopidogrel group, the clopidogrel combined with tongxinluo group, and the ticagrelor group, while the incidence of hemorrhage in the ticagrelor group was higher. CONCLUSIONS Adjusting the dose or combining with other drugs improves the efficacy of anti-platelet therapy and reduces the incidence of ischemic events after PCI.

Lipoprotein-associated phospholipase A2 and risks of coronary heart disease and ischemic stroke in the general population: A systematic review and meta-analysis.

BACKGROUND: This study investigated the associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risks of coronary heart disease (CHD) and ischemic stroke (IS) in the general population. METHODS: PubMed, Embase, and the Cochrane Library databases were searched for prospective cohort studies published prior to June 2016. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for CHD and IS risks according to Lp-PLA2 activity or mass were extracted, pooled, and weighted using random-effects modeling. RESULTS: Twelve studies examining Lp-PLA2 activity or mass and long-term risks of CHD and IS were included. Combined HRs for CHD and IS risks for the highest category referring to lowest category of Lp-PLA2 were 1.46 (95% CI: 1.20-1.78, P<0.001) and 1.58 (95% CI: 1.21-2.07, P=0.001), respectively. The same patterns were observed for both mass and activity, with the exception of those for CHD. For every 1-standard deviation (SD) increase in Lp-PLA2 activity, CHD risk increased by 12% (HR: 1.12, 95% CI: 1.05-1.22, P=0.002); no association between 1-SD increases in Lp-PLA2 activity and IS was observed. Lp-PLA2 mass was associated with CHD risk (HR: 1.02-1.24, 95% CI: 1.02-1.24, P=0.021). Lp-PLA2 mass per 1-SD increase was not associated with IS risk. CONCLUSIONS: Greater Lp-PLA2 activity or mass was associated with an increased risk of CHD and IS; however, additional well-designed trials are warranted to confirm this association.

Association between PPAP2B gene polymorphisms and coronary heart disease susceptibility in Chinese Han males and females.

Little is known about gender-related differences in the association between PPAP2B single nucleotide polymorphisms (SNPs) and coronary heart disease (CHD) in Chinese Han males and females. We therefore conducted a case-control study with 456 cases and 685 healthy controls divided into male and female subgroups. Five PPAP2B polymorphisms (SNPs) were selected and genotyped using Sequenom Mass-ARRAY technology. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age and gender. Allelic model analysis revealed that for PPAP2B rs1759752, allele frequency distributions differed between cases and controls in the male subgroup (p = 0.015, OR: 1.401, 95%CI: 1.066-1.481). Genetic model analysis revealed that in the male subgroup, rs1759752 was associated with increased CHD risk in the dominant model (p = 0.035) and overdominant model (p = 0.045). In the female subgroup, rs12566304 was associated with a decreased CHD risk in the codominant model (p = 0.038) and overdominant model (p = 0.031). Additionally, the "GC" haplotypes of rs1759752 and rs1930760 were protective against CHD in males. These observations shed new light on gender-related differences in the association between PPAP2B gene polymorphisms and CHD susceptibility in the Chinese Han population.

Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ω-Hydroxylases.

Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(ω)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas ω-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH). CRH prevents the potential harm associated with transient ischemia. The beneficial effects of EETs are reduced after their hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). ω-terminal HETEs are formed by ω-hydroxylase family members. The relationship among endothelial over-expression of sEH (Tie2-sEH Tr), the changes in oxylipins it may produce, the pharmacologic inhibition of ω-hydroxylases, activation of PPARγ, and CRH response to a brief ischemia is not known. We hypothesized that CRH is attenuated in isolated mouse hearts with endothelial sEH over-expression through modulation of oxylipin profiles, whereas both inhibition of ω-hydroxylases and activation of PPARγ enhance CRH. Compared to WT mice, Tie2-sEH Tr mice had decreased CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05), whereas inhibition of ω-hydroxylases increased these same CRH parameters in Tie2-sEH Tr mice. Inhibition of sEH with t-AUCB reversed the decreased CRH in Tie2-sEH Tr mice. Endothelial over-expression of sEH significantly changed oxylipin profiles, including decreases in DHETs, mid-chain HETEs, and prostaglandins (P < 0.05). Treatment with rosiglitazone, PPARγ-agonist, enhanced CRH (P < 0.05) in both Tie2-sEH Tr and wild type (WT) mice. These data demonstrate that endothelial over-expression of sEH (through changing the oxylipin profiles) attenuates CRH, whereas inhibition of ω-hydroxylases and activation of PPARγ enhance it.

Lipoprotein-associated phospholipase A2 in coronary heart disease: Review and meta-analysis.

BACKGROUND: Risk associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) and adverse outcomes in patients with coronary heart disease (CHD) remain unclear. The aim of the meta-analysis was to investigate the association between Lp-PLA2 and prognosis of CHD. METHODS: PubMed and Embase were examined for prospective studies published before June 2016. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of adverse outcomes according to Lp-PLA2 activity or mass were extracted, pooled, and weighted using generic inverse-variance and random-effect modeling. RESULTS: Fifteen studies with 30,857 participants were included. Overall, higher Lp-PLA2 activity or mass was not significantly related to increased risk of long-term all-cause mortality. However, higher Lp-PLA2 activity or mass was independently associated with an increased risk of long-term cardiovascular events, with pooled HR for cardiovascular events of 1.55 (95% CI, 1.08-2.23; P=0.018) and 1.62 (95% CI, 1.09-2.41; P=0.017), respectively. The prognostic value of Lp-PLA2 in predicting cardiovascular events was observed in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2. CONCLUSIONS: Greater Lp-PLA2 activity or mass was independently associated with cardiovascular events in patients with CHD, particularly in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2.

Glutathione S-Transferase T1 (GSTT1) Null Polymorphism, Smoking, and Their Interaction in Coronary Heart Disease: A Comprehensive Meta-Analysis.

BACKGROUND: The association between glutathione S-transferase T1 (GSTT1) null polymorphism and coronary heart disease (CHD) is inconsistent among studies, and data on the GSTT1 null genotype-smoking interplay in CHD is lacking. We conducted this meta-analysis to investigate the relationship between GSTT1 null polymorphism and CHD and to assess the potential interaction between GSTT1 null genotype and smoking. METHODS: PubMed and EMBASE databases were searched up to 27 January 2016 using the appropriate terms. Odds ratios were pooled using either fixed-effects or random-effects models. RESULTS: Twenty-nine articles including 31 studies with 15,004 cases and 35,597 controls were eligible. The random-effects model showed that the GSTT1 null genotype was associated with increased CHD risk (OR=1.213, 95%CI: 1.004-1.467; I2=90.4%). After excluding 10 studies detected by Galbraith plot, the fixed effects summary estimate also showed an increased risk of CHD (OR=1.14, 95% CI: 1.06-1.22; I2=27.7%). A case-only analysis including eight studies showed a statistically significant positive interaction between GSTT1 null polymorphism and smoking status on CHD (OR=1.34, 95% CI: 1.09-1.64; I2=0%). Sensitivity analyses further supported the associations. No publication bias was observed. CONCLUSIONS: This meta-analysis suggests that GSTT1 null polymorphism is associated with the risk of CHD. To our knowledge, this is the first meta-analysis to prove a positive effect of the interaction between GSTT1 null genotype and smoking status on the risk of CHD. Future studies with detailed individual information are needed to confirm our findings.

Synergistic Effect of Lipoprotein-Associated Phospholipase A2 with Classical Risk Factors on Coronary Heart Disease: A Multi-Ethnic Study in China.

AIMS: We evaluated the synergistic effect of lipoprotein-associated phospholipase A2 (Lp-PLA2) in association with classical risk factors in predicting coronary heart disease (CHD) and demonstrated the diagnostic value of Lp-PLA2 for predicting coronary stenotic lesions in subjects with CHD. METHODS: Blood samples were acquired from 911 consecutive adult subjects (662 males and 249 females) from 11 ethnic groups. Lp-PLA2 plasma levels were detected using a commercially available turbidimetric immunoassay (TIA). CHD in patients was confirmed using coronary angiography, and the severity of coronary atherosclerosis was assessed using the Gensini scoring system. RESULTS: A binary logistic regression was performed to analyse the relationships between Lp-PLA2 and other risk factors. A multivariate logistic regression analysis revealed that Lp-PLA2 levels were significantly associated with CHD (OR, 1.882; 95% CI, 1.369-2.587, p=0.000).The area under the receiver operating characteristic curve for Lp-PLA2 was 0.589 (95%CI, 0.549-0.629, p=0.000).The synergism between Lp-PLA2 and other risk factors was also investigated. The proportion of CHD attributable to the interaction between Lp-PLA2 and age was as high as 64%. CONCLUSIONS: Lp-PLA2 levels in human plasma were positively associated with the severity of CHD, and there was a clear positive interaction between Lp-PLA2 and classical risk factors in predicting CHD.

Heme oxygenase-1 gene promoter polymorphisms are associated with coronary heart disease and restenosis after percutaneous coronary intervention: a meta-analysis.

Numerous published studies have suggested that there is association between heme oxygenase-1 (HO-1) gene polymorphisms and coronary heart disease (CHD) or restenosis (RS) after percutaneous coronary intervention (PCI). This study aimed to clarify this association using a meta-analysis method. We used a systematic search for studies on the association of HO-1gene polymorphisms with CHD or RS in PubMed, Web of Science, the Cochrane Library, Wanfang Data and CNKI (China National Knowledge Infrastructure). We used Stata 12.0 software to perform the meta-analyses. Twenty-three studies, involving 12,130 patients with CHD or RS and 14,181 controls, were included. A statistically significant association between the HO-1(GT)n repeat length polymorphism and CHD was observed under allelic (odds ratio (OR) = 0.929, 95% confidence interval (CI) = 0.881-0.978, p= 0.005), recessive (OR = 0.858, 95%CI = 0.780-0.945, p= 0.002), and co-dominant (OR = 0.843, 95%CI = 0.754-0.942, p= 0.003) models. Moreover, we also found a statistically significant association between the HO-1(GT)n repeat length polymorphism and RS under allelic (OR = 0.718, 95%CI = 0.541-0.953, p= 0.022) and co-dominant (OR = 0.522, 95%CI = 0.306-0.889, p=0.017) models. We found a significant association of the HO-1T(-413)A single-nucleotide polymorphism (SNP) with CHD under allelic (OR = 0.915, 95%CI = 0.842-0.995, p= 0.038), recessive (OR = 0.869, 95%CI = 0.760-0.994, p= 0.041), and co-dominant (OR = 0.792, 95%CI = 0.663-0.946, p=0.010) models. Our study indicates that both the HO-1(GT)n repeat length polymorphism and the T(-413)A SNP are associated with decreased risk of CHD. The (GT)n repeat length polymorphism was associated with RS following PCI.