[Show abstract][Hide abstract] ABSTRACT: Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway.
PLoS ONE 10/2015; 10(10):e0141464. DOI:10.1371/journal.pone.0141464 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Impaired glucose regulation (IGR), containing prediabetes and diabetes, is an inflammatory disease. The interleukin-33 (IL-33)/IL-1 receptor-like 1 and IL-1/IL-1 receptor (IL-1R) pathways are involved and play opposite roles. While the IL-1R-associated protein (IL-1Rap) is indispensible for the two pathways, the association between the single-nucleotide polymorphisms (SNPs) of the IL-1Rap gene and IGR has not been determined. TaqMan probe quantitative polymerase chain reaction was used to genotype 11 SNPs in the regions of the IL-1Rap gene selected on the basis of linkage disequilibrium using the HapMap database in a study of 889 individuals (156 IGR patients in the case group and 733 non-diabetic patients in the control group). Logistic regression was applied to control the potential confounders in the multivariate analysis. Among 11 SNPs, IL-1Rap rs3773958 was associated with IGR. Further analysis showed that the odds ratios for GT and GT + GG carriers vs. TT carriers were 1.686 and 1.669, respectively, adjusted for gender, age, weight, waist, drinking, smoking, hypertension, alanine aminotransferase, total cholesterol and triglycerides. For rs3773958 in the non-smoking subgroup, GT and GT + GG carriers had a significantly higher risk of IGR compared to the TT carriers. The same conclusions were drawn using data from non-drinking and non-overweight subgroups. However, interactions between rs3773958 and smoking, drinking or being overweight were not significant. In conclusion, rs3773958 in the IL-1Rap gene region was associated with IGR.
[Show abstract][Hide abstract] ABSTRACT: Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell accumulation in AAA lesions that produce inflammatory cytokines and advance its pathogenesis. Peripheral cytokines may predict the degree or risk of AAA.
ELISA determined plasma interleukin-6 (IL6), IL10, IL17A, IFN-γ, and C-reactive protein (CRP) from 476 AAA patients and 200 controls. AAA patients had lower IL6, IFN-γ, IL10, IL17A, and higher CRP than controls. IL10 correlated positively with IFN-γ, IL17A, or IL6, but not CRP in control or AAA populations. IL10 associated negatively with systolic blood pressure, whereas CRP associated positively with diastolic blood pressure and body mass index. CRP was an independent AAA risk factor and correlated positively with aortic diameters before and after adjustments for other risk factors. IFN-γ, IL17A, and CRP correlated positively with cross-sectional AAA area after adjustment. IL10 correlated positively with AAA growth rate before and after adjustment. The risk of death doubled in AAA patients with CRP levels above the median.
Reduced IFN-γ, IL10, and IL17A in AAA patients, positive correlations of IFN-γ and IL17A with cross-sectional AAA area, IL10 with AAA growth rate, and IL10 with IFN-γ and IL17A suggest combined Th1, Th2, and Th17 immune responses in human AAAs.
Annals of Medicine 04/2015; 47(3):1-8. DOI:10.3109/07853890.2015.1019916 · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The IL-33/ST2 signaling pathway plays an important role in coronary artery disease (CHD); however, few studies have explored how variants in IL-33/ST2 genes influence CHD risk. Here, we examined the association between genetic variants in IL-33, ST2, and IL-1RAcP of the IL-33/ST2 axis and the risk of CHD. We conducted a case-controlled study with 1146 CHD cases and 1146 age- and sex-frequency-matched controls. Twenty-eight single nucleotide polymorphisms (SNPs) in IL-33, ST2, and IL-1RAcP were genotyped by Sequenom MassArray and TaqMan assay. Logistic regression was used to analyze these associations. The SNP rs4624606 in IL-1RAcP was nominally associated with CHD risk. The AA genotype was associated with a 1.85-fold increased risk of CHD (95% confidence interval (CI) = 1.01-3.36; p = 0.045) compared to the TT genotype. Further analysis showed that AA carriers also had a higher risk of CHD than TT + TA carriers (odds ratio (OR) = 1.85; 95% CI = 1.85-3.35; p = 0.043). However, no significant association was observed between variants in IL-33/ST2 genes and CHD risk. Further studies are needed to replicate our results in other ethnic groups with larger sample size.
International Journal of Molecular Sciences 12/2014; 15(12):23227-23239. DOI:10.3390/ijms151223227 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Circulating microRNAs (miRNAs) are emerging as novel disease biomarkers. We aimed to explore the association between circulating miRNAs and the occurrence of acute myocardial infarction (AMI) in Chinese populations.
-In the discovery stage, the plasma of 20 AMI patients and 20 controls were pooled respectively and profiled by massively parallel sequencing. Seventy-seven miRNAs showed differential expression. Selected miRNAs were validated in 178 AMI patients and 198 controls using quantitative reverse transcriptase polymerase chain reaction assays, and further replicated in 150 AMI patients and 150 controls. Results suggest that miR-320b and miR-125b levels were significantly lower in AMI patients than controls in both validation populations (p<0.0001). Lower levels of miR-320b and miR-125b were associated with increased occurrence of AMI (adjusted odds ratio [OR] 4.71, 95% confidence interval [CI] 2.96 to 7.48; OR 4.27, 95% CI 2.84 to 6.41, respectively). Addition of the two miRNAs to traditional risk factors led to a significant improvement in the area under the curve from 0.822 (95% CI, 0.787-0.856) to 0.871 (95% CI, 0.842-0.900), with a net reclassification improvement of 20.45% (p<0.0001) and an integrated discrimination improvement of 0.16 (p<0.0001) for AMI patients. A functional study showed that miR-320b and miR-125b could regulate the expression profiles of genes enriched in several signal transduction pathways critical for CHD in human vascular endothelial cells.
-The plasma levels of miR-320b and miR-125b were significantly lower in AMI patients compared with controls, and these miRNAs may be involved in the pathogenesis of coronary heart disease.
[Show abstract][Hide abstract] ABSTRACT: Aims:
Studies indicated that body iron stores were associated with coronary heart disease (CHD). Type 2 transferrin receptor (TFR2) participates in cellular iron overload and is related to cardiovascular disease. No studies investigated the associations between variants in TFR2 gene and CHD risk.
We sought to investigate this association in a Chinese Han population and performed a case-control study recruiting 1264 CHD patients and 1264 age and sex frequency matched controls. TaqMan single nucleotide polymorphisms (SNP) allelic discrimination was used to examine genotypes of the tagging single nucleotide polymorphisms (tagSNPs) of TFR2. The plasma ferritin levels were measured by ELISA.
We did not find significant associations between variants of TFR2 gene (including tagSNPs rs2075674 and rs7385804) and the risk of CHD. After adjustment for the conventional risk factors of CHD, such as smoking and age, the results did not materially alter. Interaction analyses indicated that there were no significant interactions between conventional risk factors of CHD and these two tagSNPs on CHD risk. Among different genotypes of these two tagSNPs, no significant differences in plasma ferritin levels were found.
In summary, the variants of rs2075674 and rs7385804 in TFR2 gene were not associated with CHD risk in a Chinese Han population.
Journal of Cardiovascular Medicine 06/2013; 15(5). DOI:10.2459/JCM.0b013e32836206f3 · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na+ channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations. We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-ΔKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/ΔKPQ mutations. Scn5a+/ΔKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/ΔKPQ mice. Isolated Scn5a+/ΔKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na+ currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/ΔKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na+ channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na+ currents.
[Show abstract][Hide abstract] ABSTRACT: Although (GT) ( n ) repeats in heme oxygenase-1 (HO-1) promoter may modulate gene transcriptional activity, the association between (GT) ( n ) repeats polymorphism and risk of coronary heart disease (CHD) from different levels of oxidative stress (OS) is unknown. We determined the allelic frequencies of (GT) ( n ) repeats in the HO-1 gene promoter and plasma malonaldehyde (MDA) as biomarkers of OS in 2,298 pairs of CHD patients and controls in the Chinese population. Furthermore, we measured MDA in culture mediums and HO-1 expressions levels in cell lysates of endothelial cells carrying various (GT) ( n ) genotypes under different concentrations of H(2)O(2). Compared with L/L genotype (>25 repeats) carriers, the adjusted odd ratios for S/S genotype (≤25 repeats) in subjects with different levels of OS (MDA < 1.83, 1.83-2.91, >2.91 μmol/L) were 1.06 (95%CI, 0.75 to 1.49), 0.79 (95%CI, 0.55 to 1.12), and 0.60 (95%CI, 0.44 to 0.81), respectively (P (interaction) = 0.002). In biological experiments, compared with endothelial cells carrying L/L genotype, cells with S/S genotype did not have a significantly higher HO-1 expression under 0 μmol/L H(2)O(2), but displayed a significantly higher HO-1 expression under 50 μmol/L H(2)O(2) (P (interaction) = 0.003). S/S genotype in HO-1 gene promoter is associated with a lower risk of CHD in subjects with higher levels of OS, because under conditions of high OS, the S/S genotype has higher levels of HO-1, an antioxidant.
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population.
We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10(-8)), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10(-4) and 0.001, respectively).
We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.
PLoS ONE 11/2011; 6(11):e27481. DOI:10.1371/journal.pone.0027481 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Associations between "lipid-related" candidate genes, blood lipid concentrations and coronary artery disease (CHD) risk are not clear. We aimed to investigate the effect of three newly identified lipids loci from genome-wide association studies on CHD and blood lipid levels in Chinese Han population. The genotypes of SNPs at three newly identified lipid loci and blood lipids concentrations were examined in 1360 CHD patients and 1360 age- and sex-frequency matched controls from an unrelated Chinese Han population. Allele T of rs16996148 occurred less frequently in CHD patients with the odds ratio (OR) being 0.64 (95% CI 0.50 to 0.81), after adjusting for conventional risk factors and was associated with a 33% decreased CHD risk (P<0.01) comparing with the major allele G. Individuals with GT genotype had the lowest CHD risk. No associations were found between the polymorphisms of other two loci with CHD risk and all three SNPs had no effect on lipid profile in this population. SNP rs16996148 on chromosome 19p13 is significantly associated with lower risk for CHD in Chinese Han population. However, it remains unresolved why these lipid-related loci had significantly less effects than the correspondingly expected effects on blood lipids levels in this population.
Journal of Huazhong University of Science and Technology 08/2011; 31(4):452-6. DOI:10.1007/s11596-011-0472-6 · 0.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is ample evidence that Hsp70 takes part in the progress of coronary heart disease (CHD). This implies that genetic variants of Hsp70 genes such as HSPA8 (HSC70) gene might contribute to the development of CHD. The present study aimed to investigate whether certain genetic variants of HSPA8 gene are associated with CHD in Han Chinese people.
A total of 2006 subjects (1003 CHD cases and 1003 age- and sex- matched healthy controls) were recruited. Genetic variants in the HSPA8 gene were identified by sequencing of the gene in 60 unrelated Chinese. Four tag single nucleotide polymorphisms (tagSNPs) (rs2236659, rs2276077, rs10892958, and rs1461496) were selected and genotyped. The function of the significant SNP was evaluated using luciferase reporter assays in two cell lines. By sequencing the promoter and all exons and introns of the HSPA8 gene, 23 genetic variants were identified. One promoter SNP rs2236659 was associated with susceptibility to CHD. Carriers of the "C" allele of rs2236659 had decreased CHD risk with odds ratio (OR) of 0.78 (95% CI: 0.62, 0.98; P = 0.033) after adjustment for conventional risk factors. Haplotype analyses indicated that haplotype GCGC contributed to a lower CHD risk (OR = 0.78, 95% CI: 0.65, 0.93; P = 0.006) compared with the common haplotype AGGT. In a transfection assay, the C allele of rs2236659 showed a 37-40% increase in luciferase expression of the reporter gene luciferase in endothelial and non-endothelial cells compared with the T allele.
These findings suggest that genetic variants in HSPA8 gene (especially promoter SNP rs2236659) contribute to the CHD susceptibility by affecting its expression level.
PLoS ONE 03/2010; 5(3):e9684. DOI:10.1371/journal.pone.0009684 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although immune reactions against heat shock proteins have been implicated in the pathogenesis of atherosclerosis, conflicting associations between Hsp70, anti-Hsp70 antibody and coronary heart disease (CHD) have been reported. This study assessed whether there is a significant association between extracellular human Hsp70, anti-Hsp70 antibody and acute coronary syndrome (ACS) and stable angina (SA), and examined dynamic changes in Hsp70 and anti-Hsp70 antibody levels induced by acute myocardial infarction (AMI). Plasma Hsp70 and anti-Hsp70 antibody levels in 291 patients with ACS (179 AMI, 112 unstable angina), 126 patients with SA and 417 age and sex-matched healthy subjects, and in 40 patients after admission for AMI, and on day 2, 3, and 7 after the onset of AMI were determined using enzyme-linked immunosorbent assays. Hsp70 levels were significantly higher in ACS and SA and anti-Hsp70 antibody levels were only markedly lower in ACS than controls. After adjustment for traditional CHD risk factors, increasing levels of Hsp70 were significantly associated with an increased risk and severity of ACS (P for trend < 0.001), whereas increasing levels of anti-Hsp70 antibody were associated with a decreased risk of ACS (P for trend = 0.0003). High levels of Hsp70 combined with low levels of anti-Hsp70 antibody had a joint effect on the risk of ACS (OR, 5.14, 95% CI, 3.00-8.79; P < 0.0001). In patients with AMI, Hsp70 levels decreased rapidly from days 1-7 after onset, whereas anti-Hsp70 antibody levels increased in patients with AMI. These findings suggest that higher Hsp70 levels or lower anti-Hsp70 antibody levels are independently associated with a higher risk of ACS. Higher Hsp70 levels and lower anti-Hsp70 antibody levels combine to further increase this risk.
[Show abstract][Hide abstract] ABSTRACT: Natriuretic peptide precursor A (NPPA) is synthesized, stored, and released by atrial myocytes. Previous studies have shown
that NPPA plays a significant role in the regulation of coronary circulation and in atherosclerosis. Rs5065 NPPA gene polymorphism
leads to the translation of NPPA with two additional arginines and has been suggested to be associated with salt-sensitive
hypertension. The purpose of the present study was to investigate the relationship between the rs5065 NPPA gene polymorphism
and the risk of coronary heart disease (CHD) in Chinese Han population. We genotyped the single nucleotide polymorphism (SNP)
rs5065 NPPA in the human NPPA gene in 1861 sex- and age-matched subjects, comprising of 904 CHD cases and 957 controls of
Chinese Han population. Genotyping of SNP was performed with Taqman SNP allelic discrimination assays by means of an ABI 7900HT.
Our study showed that the frequencies of rs5065 NPPA C allele in the case and the control groups were 0.012 and 0.005, respectively.
There was significant difference in C allele frequency distribution between the two groups (OR = 2.607, 95% CI: 1.197–5.678,
P = 0.012). In the case group, there was significant difference between smokers and nonsmokers with subjects carrying C allele
(P = 0.037), and no significant difference in gender, age, fasting total cholesterol (TC), triglycerides (TG), fasting plasma
glucose (FPG), body mass index (BMI), and blood pressure (BP) between the cases and the controls (P>0.05). Our results suggest that the C allele of rs5065 NPPA gene polymorphism may be associated with the risk of CHD.
Frontiers of Medicine in China 12/2009; 3(4):437-442. DOI:10.1007/s11684-009-0074-x
[Show abstract][Hide abstract] ABSTRACT: The relation between the expression and activity of MMP-9 in C-reactive protein (CRP)-induced human THP-1 mononuclear cells and the activation of nuclear factor kappa-B (NF-kappaB) was studied to investigate the possible role of CRP in plaque destabilization. Human THP-1 cells were incubated in the presence of CRP at 0 (control group), 25, 50 and 100 microg/mL (CRP groups) for 24 h. In PDTC (a specific NF-kappaB inhibitor) group, the cells were pre-treated with PDTC at 10 micromol/L and then with 100 microg/mL CRP. The conditioned media (CM) and human THP-1 cells in different groups were harvested. MMP-9 expression in CM and human THP-1 cells was measured by ELISA and Western blotting. MMP-9 activity was assessed by fluorogenic substrates. The expression of NF-kappaB inhibitor alpha (IkappaB-alpha) and NF-kappaB P(65) was detected by Western blotting and ELISA respectively. The results showed that CRP increased the expression and activity of MMP-9 in a dose-dependent manner in the human THP-1 cells. Western blotting revealed that IkappaB-alpha expression was decreased in the cells with the concentrations of CRP and ELISA demonstrated that NF-kappaB P65 expression in the CRP-induced cells was increased. After pre-treatment of the cells with PDTC at 10 micromol/L, the decrease in IkappaB-alpha expression and the increase in NF-kappaB P(65) expression in the CRP-induced cells were inhibited, and the expression and activity of MMP-9 were lowered too. It is concluded that increased expression and activity of MMP-9 in CRP-induced human THP-1 cells may be associated with activation of NF-kappaB. Down-regulation of the expression and activity of MMP-9 may be a new treatment alternative for plaque stabilization by inhibiting the NF-kappaB activation.
Journal of Huazhong University of Science and Technology 09/2009; 29(4):399-403. DOI:10.1007/s11596-009-0401-0 · 0.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Licorice has been used to treat many ailments including cardiovascular disorders in China for long time. Recent studies have shown that the cardiac actions of licorice have been attributed to its active component, glycyrretinic acid (GA). However, its mechanism remains poorly understood.
The effects of GA on the cardiac sodium currents (I(Na)), L-type calcium currents (I(Ca,L)) and hyperpolarization-activated inward currents (I(f)) were investigated.
Human isoforms of wild-type and DeltaKPQ-mutant type sodium channels were expressed in Xenopus oocytes, and the resulting currents (peak and late I(Na)) were recorded using a two-microelectrode voltage-clamp technique. A perforated patch clamp technique was employed to record I(Ca,L) and I(f) from isolated rabbit sinoatrial node pacemaker cells.
GA inhibited peak I(Na) (33% at 90 microM) and late I(Na) (72% at 90 microM), but caused no significant effects on I(Ca,L) and I(f).
GA blocked cardiac sodium currents, particularly late I(Na.) Our findings might help to understand the traditional use of licorice in the treatment of cardiovascular disorders, because reduction of sodium currents (particularly late I(Na)) would be expected to provide protection from Na(+)-induced Ca(2+) overload and cell damage.
Journal of ethnopharmacology 07/2009; 125(2):318-23. DOI:10.1016/j.jep.2009.06.016 · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HSP70 plays crucial roles in endothelial cell apoptosis, which is involved in the early phase and progress of coronary heart disease (CHD). However, the association between polymorphisms of HSP70 genes and the risk of CHD still remains unclear. Our aim was to determine whether genetic variants in the HSPA1A gene are associated with the risk of CHD.
By resequencing and genotyping, the associations of 2 single nucleotide polymorphisms (SNPs) +190G/C (rs1043618) and -110A/C (rs1008438) in the HSPA1A gene with risk of CHD were determined in a 1,003 pairs case-control study. The SNP function was further analyzed using a luciferase reporter assay in two cell lines. The results indicated that +190CC genotype was associated with significantly higher risk of CHD when compared with +190GG genotype (OR = 1.56, 95% CI: 1.10-2.20, P = 0.012), while association between -110A/C polymorphism and CHD was not statistically significant (P>0.05). However, the -110C/+190C haplotype had a significantly higher risk of CHD when compared with the -110A/+190G haplotype (OR = 1.17, 95% CI: 1.01-1.34, P = 0.031). Luciferase reporter assays showed that the +190C allele resulted in 14% ~ 45% reduction in luciferase expression in endothelial and non-endothelial cells when compared with the +190G allele.
The identified genetic variants in the HSPA1A gene combinatorially contribute towards the susceptibility to CHD likely by affecting the level of synthesis of HSP70. This study may provide useful markers for identification of subjects at risk for CHD.
PLoS ONE 02/2009; 4(3):e4851. DOI:10.1371/journal.pone.0004851 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although heat shock protein 60 (Hsp60) is implicated in the pathogenesis of atherosclerosis, its role in coronary heart disease (CHD) is uncertain. This study explored the influence of circulating Hsp60 on CHD in a large case-control study, as well as the impact of acute myocardial infarction on Hsp60 levels in a prospective study.
Plasma Hsp60 and anti-Hsp60 antibody levels were determined by immunoassay. In the case-control study (1003 patients with CHD, 1003 matched control subjects), Hsp60 levels were higher in patients with CHD and were related to CHD (OR comparing extreme quartiles=4.14, P<0.0001). This association remained after adjustment for traditional risk factors (P for trend <0.0001). Individuals having high levels of Hsp60 (greater than the median of 160.24 ng/mL) and anti-Hsp60 antibody (greater than the median of 38.42 U/mL) were at a greater risk of CHD than those with low levels (OR 2.30, P<0.0001). Stronger additive effects (OR 14.04, P<0.0001) were apparent at higher Hsp60 and anti-Hsp60 antibody levels (>1000 ng/mL and greater than the median of 38.42 U/mL, respectively). The simultaneous presence of high Hsp60 and anti-Hsp60 antibody levels, current smoking, hypertension, and diabetes were cumulatively associated with CHD. Individuals who had any 4 or more of these 5 factors had an OR of 38.61 for CHD (P<0.0001) compared with individuals who had none of these factors. For the prospective study, blood was drawn from 20 patients immediately after admission for acute myocardial infarction and 2, 3, and 7 days thereafter. Hsp60 levels were significantly higher on the day of and the day after arrival than 7 days after an acute myocardial infarction (P=0.011 and P=0.026, respectively).
Elevated Hsp60 levels are associated with an increased risk for CHD, and Hsp60 and anti-Hsp60 antibody levels combine to increase this risk. In addition, acute myocardial infarction induces Hsp60 release.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to characterize the role of the late Na+ current (I(Na,L)) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, I(Na,L). In sixteen hearts studied, exposure to 1-10nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early after depolarisations, delayed after depolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n=5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 microM ranolazine in intact hearts (n=11) and isolated sino-atrial preparations (n=5). In conclusion, the I(Na,L) enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the I(Na,L) blocker, ranolazine (10 microM). The results suggest that I(Na,L) blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.
Progress in Biophysics and Molecular Biology 10/2008; 98(2-3):198-207. DOI:10.1016/j.pbiomolbio.2009.01.003 · 2.27 Impact Factor