Jian-Jun Yan

Plasma levels of lipometabolism-related miR-122 and miR-370 are increased in patients with hyperlipidemia and associated with coronary artery disease

BackgroundHyperlipidemia plays a crucial role in the development and progression of coronary artery disease (CAD). Recent studies have identified that microRNAs (miRNAs) are important regulators of lipid metabolism, but little is known about the circulating levels of lipometabolism-related miRNAs and their relationship with the presence of CAD in patients with hyperlipidemia.MethodsIn the present study, we enrolled a total of 255 hyperlipidemia patients with or without CAD and 100 controls with normal blood lipids. The plasma levels of four known lipometabolism-related miRNAs, miR-122, miR-370, miR-33a, and miR-33b were quantified by real-time quantitative PCR. Blood levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol were determined. Furthermore, the severity of CAD was assessed with the Gensini score system based on the degree of luminal narrowing and its geographic importance.ResultsOur results revealed for the first time that plasma levels of miR-122 and miR-370 were significantly increased in hyperlipidemia patients compared with controls, and the levels of miR-122 and miR-370 were positively correlated with TC, TG, and LDL-C levels in both hyperlipidemia patients and controls. Multiple logistic regression analysis demonstrated that the increased levels of miR-122 and miR-370 were associated with CAD presence, even after adjustment for other cardiovascular risk factors. Furthermore, miR-122 and miR-370 levels were positively correlated with the severity of CAD quantified by the Gensini score. However, both miR-33a and miR-33b were undetectable in plasma.ConclusionsOur results suggest that increased plasma levels of miR-122 and miR-370 might be associated with the presence as well as the severity of CAD in hyperlipidemia patients.

Black and green tea consumption and the risk of coronary artery disease: a meta-analysis

BACKGROUND Epidemiologic studies are inconsistent regarding the association between tea consumption and the risk of coronary artery disease (CAD). OBJECTIVE The objective was to perform a meta-analysis to determine whether an association exists between tea consumption and total CAD endpoints in observational studies. DESIGN We searched PUBMED and EMBASE databases for studies conducted from 1966 through November 2009. Study-specific risk estimates were combined by using a random-effects model. RESULTS A total of 18 studies were included in the meta-analysis: 13 studies on black tea and 5 studies on green tea. For black tea, no significant association was found through the meta-analysis [highest compared with lowest, summary relative risk (RR): 0.92; 95% CI: 0.82, 1.04; an increment of 1 cup/d, summary RR: 0.98; 95% CI: 0.94, 1.02]. For green tea, the summary RR indicated a significant association between the highest green tea consumption and reduced risk of CAD (summary RR: 0.72; 95% CI: 0.58, 0.89). Furthermore, an increase in green tea consumption of 1 cup/d was associated with a 10% decrease in the risk of developing CAD (summary RR: 0.90; 95% CI: 0.82, 0.99). CONCLUSIONS Our data do not support a protective role of black tea against CAD. The limited data available on green tea support a tentative association of green tea consumption with a reduced risk of CAD. However, additional studies are needed to make a convincing case for this association.

The common variant in the GSTM1 and GSTT1 genes is related to markers of oxidative stress and inflammation in patients with coronary artery disease: a case-only study.

Recent studies suggest that the common variant in the GSTM1 and GSTT1 genes modifies the risk of coronary artery disease (CAD), however, it is unclear whether the risk of CAD modulated by variants in the GSTM1 and GSTT1 genes was associated with alterations of indices of oxidative stress and inflammation. Our study is an attempt to provide insight into the role of GST genetic variant and markers of oxidative stress and inflammation in CAD patients. A total of 719 Chinese CAD patients were successfully genotyped. Plasma total antioxidant status (TAOS), glutathione(GSH), C-reactive protein (CRP), fibrinogen (FIB) and white blood cell count (WBC) were determined to evaluate the oxidative stress and inflammatory response. The correlations between GSTM1/GSTT1 genotypes and alterations of indices of oxidative stress and inflammation were analyzed. We found GSTM1-0/GSTT1-0 subjects had higher CRP and FIB and lower TAOS compared to patients with wild-type GSTM1/GSTT1 genes. A stepwise elevations in age, the incidences of hypertension and diabetes mellitus, levels of FIB and the number of WBC were associated with increased number of stenosed vessels. Reductions of plasma TAOS and GSH were associated with increased number of stenosed vessels. Our results suggest that GST polymorphisms maybe modify the effect on markers of oxidative stress and inflammation in Chinese CAD patients.

Association of GSTM1 and GSTT1 gene polymorphisms with coronary artery disease in relation to tobacco smoking

Abstract Background: Recent studies suggest that the common variant in the glutathione S-transferase (GST) M1 (GSTM1) and T1 (GSTT1) gene is associated with the risk of smoking-related coronary artery disease (CAD). Intra-ethnic as well as inter-ethnic differences are known to impact the frequencies of GST gene polymorphisms, thus influencing its interactive effect with tobacco smoking on CAD risk. The aim of the present study was to evaluate the interaction of the genetic polymorphisms of GSTM1 and GSTT1 with cigarette smoking and the risk of CAD in a Chinese population. Methods: We conducted a study with 277 CAD patients and 277 controls matched by age and sex to examine the prevalence of GSTM1 and GSTT1 polymorphism in CAD. Results: We found that homozygous deletion of GSTM1 had a frequency of 32.1% among patients with CAD and 21.3% among those without CAD (p=0.004). The frequency of the GSTT1null genotype was 27.8% among the patients with CAD and 19.1% among CAD-free subjects (p=0.016). Patients who smoked having both the wild-type genotypes of GSTM1 and GSTT1 were protected from developing coronary heart disease (p<0.001). Moreover, smokers with combined GSTM1nullGSTT1null genotypes had a significantly higher number of stenosed vessels than those with the positive genotype (p=0.02). Conclusions: Our results suggest that GST polymorphisms may be a susceptibility factor to smoking-related CAD in the Chinese population. Clin Chem Lab Med 2008;46:1720–5.

Folate and risk of coronary heart disease: A meta-analysis of prospective studies

BACKGROUND AND AIMS Epidemiologic studies are inconsistent regarding the association between folate and coronary heart disease (CHD) risk. The aim was to perform a meta-analysis to determine whether an association exists between folate and total CHD endpoints in prospective studies. METHODS AND RESULTS We searched the PUBMED and EMBASE databases for studies conducted from 1966 through August 2010. Data were independently abstracted by 2 investigators using a standardized protocol. Study-specific risk estimates were combined by using a random effects model. A total of 14 studies were included in the meta-analysis: 7 studies on dietary folate intake and 8 studies on blood folate levels. For dietary intake, the summary relative risk (RR) indicated a significant association between the highest folate intake and reduced risk of CHD (summary RR: 0.69; 95% CI: 0.60, 0.80). Furthermore, an increase in folate intake of 200 ug/day was associated with a 12% decrease in the risk of developing CHD (summary RR: 0.88; 95% CI: 0.82, 0.94). For blood folate levels, we also found a borderline inverse association of highest blood folate levels on CHD risk (summary RR: 0.74; 95% CI: 0.53, 1.02); our dose-response analysis indicated that an increment in blood folate levels of 5 mmol/l was associated with an 8% decrease in the risk of developing CHD (summary RR: 0.92; 95% CI: 0.84, 1.00). CONCLUSION This meta-analysis suggests that dietary folate intake and blood folate level are inversely associated with CHD risk.

Genetic variant in visfatin gene promoter is associated with decreased risk of coronary artery disease in a Chinese population.

BACKGROUND Visfatin is a newly identified pro-inflammatory adipokine expressed predominantly in visceral fat. Previous studies have suggested a role for visfatin in low-grade inflammation and regulation of lipid metabolism. Most recently, a genetic polymorphism -1535C>T located in the visfatin gene promoter has been identified, and suggested to be associated with the regulation of visfatin expression, lipid levels. However, it is unclear whether this polymorphism has a linkage with CAD. METHODS We conducted a hospital-based case-control study with 257 CAD patients and 292 controls to examine the potential association of the Visfatin -1535C>T polymorphism with CAD. RESULTS The frequencies of the CC, CT, and TT genotypes in cases were significantly different from those of controls (chi2=6.223, P=0.045). Subjects with the variant genotypes (CT+TT) had a 40% decreased risk of CAD relative to CC carriers (adjusted OR=0.60, 95%CI=0.40-0.89). Furthermore, the adjusted OR of a TT genotype for CAD was 0.52 (95%CI=0.31-0.87). There was a significant association between Visfatin -1535C>T polymorphism and triglyceride levels in both CAD patients and controls (P=0.003, 0.018, respectively). In stratified analyses, the T allele was significantly associated with reduced risk of CAD in males, subjects with age <59years, and non-smokers. Moreover, a borderline statistical significance (P=0.058 for trend) was observed between the variant genotypes and severity of CAD. CONCLUSION Our results suggested that Visfatin -1535C>T polymorphism might be associated with reduced risk of CAD in a Chinese population.

Increased plasma levels of lncRNA H19 and LIPCAR are associated with increased risk of coronary artery disease in a Chinese population

Recent studies in animal models and humans show that long non-coding RNAs (lncRNAs) are involved in the development of atherosclerosis, which contributes to the pathological foundation of coronary artery disease (CAD). LncRNAs in plasma and serum have been considered as promising novel biomarkers for diagnosis and prognosis of cardiovascular diseases, especially CAD. We here measured the circulating levels of 8 individual lncRNAs which are known to be relevant to atherosclerosis in the plasma samples from 300 patients with CAD and 180 control subjects by using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) methods. We found that the plasma level of H19 and long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) were significantly increased in patients with CAD. The area under the receiver operating characteristic curve was 0.631 for H19 and 0.722 for LIPCAR. Multivariate logistic regression analyses indicated that plasma H19 and LIPCAR were independent predictors for CAD, even after adjustment for traditional cardiovascular risk factors. Further studies identified that plasma levels of H19 and LIPCAR were also increased in CAD patients with heart failure compared to those with normal cardiac function. Taken together, our results suggest that increased plasma levels of H19 and LIPCAR are associated with increased risk of CAD and may be considered as novel biomarkers for CAD.

Inhibition of EMMPRIN and MMP-9 Expression by Epigallocatechin-3-Gallate through 67-kDa Laminin Receptor in PMA-Induced Macrophages

Background/Aims: It is well documented that overexpression of EMMPRIN (extracellular matrix metalloproteinase inducer) and MMPs (matrix metalloproteinases) by monocytes/macrophages plays an important role in atherosclerotic plaque rupture. Green tea polyphenol epigallocatechin-3-gallate (EGCG) has a variety of pharmacological properties and exerts cardiovascular protective effects. Recently, the 67-kD laminin receptor (67LR) has been identified as a cell surface receptor of EGCG. The aim of the present study was to evaluate the effects of EGCG on the expression of EMMPRIN and MMP-9 in PMA-induced macrophages, and the potential mechanisms underlying its effects. Methods: Human monocytic THP-1 cells were induced to differentiate into macrophages with phorbol 12-myristate 13-acetate (PMA). Protein expression and MMP-9 activity were assayed by Western blot and Gelatin zymography, respectively. Real-time PCR was used to examine EMMPRIN and MMP-9 mRNA expression. Results: We showed that EGCG (10-50µmol/L) significantly inhibited the expression of EMMPRIN and MMP-9 and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and c-Jun N-terminal kinase (JNK) in PMA-induced macrophages. Downregulation of EMMPRIN by gene silencing hindered PMA-induced MMP-9 secretion and expression, indicating an important role of EMMPRIN in the inhibition of MMP-9 by EGCG. Moreover, 67LR was involved in EGCG-mediated suppression of EMMPRIN and MMP-9 expression. Anti-67LR antibody treatment led to abrogation of the inhibitory action of EGCG on the expression of EMMPRIN and MMP-9 and activation of ERK1/2, p38, and JNK. Conclusion: Our results indicate that EGCG restrains EMMPRIN and MMP-9 expression via 67LR in PMA-induced macrophages, which also suggests that EGCG may be a possible therapeutic agent for stabilizing atherosclerotic plaque.

Mechanistic insights into the link between visfatin gene C-1535T polymorphism and coronary artery disease: an in vitro study

Visfatin, a pro-inflammatory cytokine predominantly released from leucocytes, is correlated with coronary artery disease (CAD). We have previously reported that the −1535C>T polymorphism (rs1330082), which located on the promoter region of visfatin, was associated with decreased risk of CAD. Here, we investigated the underlying mechanism by which this polymorphism affects the genetic susceptibility to CAD. The difference of the promoter activities between −1535T variant and −1535C allele was tested by luciferase reporter gene assay. The difference of transcription factor binding activities between T and C allele was evaluated by electrophoretic mobility shift assay. In reporter gene assay, we showed that the T variant had a significantly reduced transcriptional activity compared with the C allele. The T-variant significantly attenuated the promoter binding affinity to nuclear transcription factors and this effect became much obvious after treatment with TNF-α. Moreover, competition experiment revealed that the retarded complex formed by T-1535- or C-1535-probe binding to nuclear extracts was nearly completely inhibited by unlabeled activator protein-1 (AP-1) specific probe, indicating that AP-1 might be the target nuclear effector. Taken together, our data provided potential mechanistic link between the visfatin −1535C>T polymorphism and reduced CAD risk.

Efficacy of equilibrium radionuclide angiography to predict acute response to cardiac resynchronization therapy in patients with heart failure.

ObjectiveTo predict the acute response to cardiac resynchronization therapy (CRT) in patients with left ventricular mechanical dyssynchrony using equilibrium radionuclide angiography (ERNA). Patients and methodsA total of 24 consecutive heart failure patients scheduled for CRT were included. ERNA was performed before and within 48 h after pacemaker implantation to calculate both left ventricular (LV) volumes and LV dyssynchrony. LV dyssynchrony was defined as the standard left ventricular phase shift and left ventricular phase standard deviation (LVPS% and LVPSD%). Patients were subsequently divided into acute responders or nonresponders, based on a reduction of at least 15% in LV end-systolic volume immediately after CRT. ResultsFifteen patients (63%) were classified as acute responders. Baseline characteristics were similar between responders and nonresponders except for the LVPS% and LVPSD%, which were larger in responders. Moreover, responders demonstrated a significant reduction of LVPS% and LVPSD% immediately after CRT (from 28.00±2.88 to 17.53±4.94 and 11.20±2.54 to 5.60±1.80, P<0.001), whereas in nonresponders LVPS% and LVPSD% remained unchanged (from 21.44±3.91 to 19.56±4.22% and 6.55±1.51 to 6.22±1.30%, P=NS). Receiver operating characteristic curve analysis revealed that a cut-off value of 25% for LVPS%, a sensitivity of 80% with a specificity of 89% were obtained to predict acute ERNA response to CRT (area under the curve=0.93) and a cut-off value of 8.5% for LVPSD%, a sensitivity of 87% with a specificity of 89% were obtained to predict acute ERNA response to CRT (area under the curve=0.95). ConclusionERNA is highly predictive for acute response to CRT. ERNA also allows assessment of changes in LV volumes and LV ejection fraction before and after CRT implantation. Video Abstract: http://links.lww.com/NMC/A40