Zofenopril versus ramipril in the early phase of acute myocardial infarction with systolic dysfunction: A retrospective study.

INTRODUCTION: Prognostic benefits of zofenopril over ramipril in the early phase of acute myocardial infarction have been reported by the SMILE study, but these benefits have not been tested in clinical practice in the Chinese population. The objective of this study was to compare the effectiveness and safety of zofenopril plus aspirin against ramipril plus aspirin in patients with acute myocardial infarction. METHODS: Patients in the early phase of acute myocardial infarction received 30 mg zofenopril (ZF cohort, N=191) or 5 mg ramipril (RP cohort, N=256) b.i.d. plus 100 mg aspirin/day. Data regarding hospitalisation for cardiovascular disease, non-cardiovascular events and mortality were collected and analysed. RESULTS: During 1 year of treatment, 47 (25%) patients in the ZF cohort and 97 (40%) patients in the RP cohort were hospitalised due to cardiovascular disease (p=0.002), and three (2%) patients in the ZF cohort and 14 (6%) patients in the RP cohort died (p=0.043). Lower incidences of dry cough (p=0.001) and anaemia (p=0.049) were reported in the ZF cohort. CONCLUSIONS: The study recommends zofenopril with 100 mg aspirin for a longer period in patients with acute myocardial infarction with systolic dysfunction.

Low Serum Adropin Levels are Associated with Coronary Slow Flow Phenomenon.

BACKGROUND: Adropin is a peptide hormone expressed in coronary artery endothelial cells, which plays a potential endothelial protective role. We sought to assess whether serum adropin levels are correlated with the coronary slow flow phenomenon (CSFP). METHODS: We enrolled 82 patients with angiographically confirmed CSFP and 184 age-matched controls. Serum adropin levels were measured by enzyme-linked immunosorbent assay (ELISA), and coronary flow rate was assessed using thrombolysis in myocardial infarction (TIMI) frame count (TFC). CSFP was defined as a corrected TIMI-TFC greater than two standard deviations from the normal range. RESULTS: Serum adropin levels were significantly lower in the CSFP patients (n = 82) than in the controls (n = 184) (4.03 ± 1.99 vs. 4.86 ± 1.88 ng/ml, p = 0.001). Multivariate logistic regression analysis revealed that serum adropin was the only independent negative predictor of CSFP (odds ratio 0.758, 95% confidence interval 0.647-0.888, p = 0.001). Serum adropin levels were independently and negatively correlated with mean TFC (r = -0.387, p < 0.001). CONCLUSIONS: We demonstrated that decreased serum adropin levels were independently associated with the presence and severity of angiographically proven CSFP. These findings suggest that serum adropin may be a potential biomarker to provide valuable information regarding the prediction of CSFP.

Matrine inhibits the expression of adhesion molecules in activated vascular smooth muscle cells.

Atherosclerosis is a chronic inflammatory disease associated with increased expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Matrine is a main active ingredient of Sophora flavescens roots, which are used to treat inflammatory diseases. However, the effects of matrine on the expression of adhesion molecules in VSMCs have largely remained elusive. Therefore, the present study investigated the effects of matrine on the expression of adhesion molecules in tumor necrosis factor (TNF)­α­stimulated human aortic smooth muscle cells (HASMCs). The results showed that matrine inhibited the expression of vascular cell adhesion molecule­1 (VCAM­1) and intercellular adhesion molecule­1 (ICAM­1) in TNF­α­stimulated HASMCs. Matrine markedly inhibited the TNF­α­induced expression of nuclear factor (NF)­κB p65 and prevented the TNF­α­caused degradation of inhibitor of NF­κB; it also inhibited TNF­α­induced activation of mitogen­activated protein kinases (MAPKs). Furthermore, matrine inhibited the production of intracellular reactive oxygen species (ROS) in TNF­α­stimulated HASMCs. In conclusion, the results of the present study demonstrated that matrine inhibited the expression of VCAM­1 and ICAM­1 in TNF­α­stimulated HASMCs via the suppression of ROS production as well as NF­κB and MAPK pathway activation. Therefore, matrine may have a potential therapeutic use for preventing the advancement of atherosclerotic lesions.

Serum salusin-ß levels are associated with the presence and severity of coronary artery disease.

OBJECTIVES: We sought to assess whether serum salusin-ß levels are correlated with the presence and severity of coronary artery disease (CAD). METHODS: We measured serum salusin-ß levels in 278 consecutive patients undergoing coronary angiography (CAG) for the evaluation of CAD and in 126 healthy controls. Serum salusin-ß levels were measured by enzyme-linked immunosorbent assay. The severity of CAD was assessed by angiographic coronary atherosclerosis index score system. RESULTS: Serum salusin-ß levels were significantly higher in patients undergoing CAG (n = 278) than those in healthy controls (n = 126) (3.81 ± 0.99 vs 4.34 ± 1.40 nmol/L, P < 0.01). In patients undergoing CAG, patients with CAD (n = 160) had significantly higher serum salusin-ß levels compared to patients without CAD (n = 118) (4.65 ± 1.44 vs 3.94 ± 1.23 nmol/L, P < 0.01). Multivariate logistic regression analysis revealed that serum salusin-ß levels were independently associated with the presence of CAD (odds ratio, 1.439; 95% confidence interval, 1.176-1.760; P < 0.01). Serum salusin-ß levels were positively correlated with the coronary atherosclerosis index score (r = 0.316, P < 0.001). CONCLUSIONS: Serum salusin-ß levels were associated with the presence and severity of CAD. Salusin-ß in serum might serve as a potential biomarker for reflecting the development and progression of CAD. Therapeutic treatment by inhibiting salusin-ß interaction to prevent CAD warrants further investigation.

Anticancer and immunoregulatory activity of Gynostemma pentaphyllum polysaccharides in H22 tumor-bearing mice.

A neutral polysaccharide fraction (CGPP) was extracted from Gynostemma pentaphyllum by water extraction and ethanol precipitation. Gas chromatography (GC) analysis showed that the CGPP was mainly composed of mannose, glucose, arabinose, rhamnose, galactose and glucuronic acid in molar ratios of 2.0:2.2:1.3:2.2:1.2:2.5. The present study aimed at evaluating the antitumor potentials of CGPP on the growth of H22 tumor transplanted in mice and the underlying mechanism. The results showed that CGPP (50 and 200mg/kg) could effectively inhibit the solid tumor growth of H22 hepatocarcinoma transplanted in ICR mice. Besides, the body weight, spleen/thymus indexes and splenocytes proliferation of H22 tumor bearing mice were also improved in CGPP-treated groups. Furthermore, the level of the cytokines, such as IL-2, TNF-α and IFN-γ, as well as the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) in tumor-bearing mice were markedly promoted by CGPP oral administration. In addition, CGPP treatment greatly prolonged the survival period in H22 ascites tumor-bearing mice. Taken together, these findings indicate that CGPP has antitumor activity in vivo at least partly via improving immune responses of host organism, and seems to be a safe and effective supplementary agent for the treatment of hepatocellular carcinoma (HCC).

Overexpression of CCN3 inhibits inflammation and progression of atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) 3 has been recently reported to play a role in regulating inflammation of vascular endothelial cells. However, the role of CCN3 in atherosclerosis, which is characterized by vascular inflammation, remains unclear. HYPOTHESIS AND OBJECTIVES: Overexpression of CCN3 may relieve the inflammation response in and inhibit the progress of atherosclerosis. We aimed to explore the potential roles of CCN3 in inflammation in atherosclerosis. STRATEGY AND MAIN RESULTS: In in vitro studies using cultured human aortic endothelial cells and human umbilical vein endothelial cells, CCN3 mRNA and protein expression significantly decreased in response to tumor necrosis factor-α and interleukin-1ß treatments (p<0.05), when analyzed by quantitative real-time polymerase chain reaction and Western blot. Using a mouse model of atherosclerosis, the mRNA and protein levels of CCN3 decreased by 72.2% (p = 0.041) and 86.4% (p = 0.036), respectively, compared with levels in wild-type control mice, respectively. Overexpression of CCN3 by adenovirus-mediated gene overexpression decreased low-density lipoprotein cholesterol by 48.9% (p = 0.017), total cholesterol by 58.9% (p = 0.031), and triglycerides by 56.8% (p = 0.022), and it increased high-density lipoprotein cholesterol level by 2.16-fold (p = 0.039), compared with control groups. Additionally, a reduced plaque area and increased fibrous cap were observed (p<0.05). Furthermore, CCN3 overexpression decreased cell adhesion molecule-1 mRNA expression by 84.7% (p = 0.007) and intercellular adhesion molecule-1 mRNA expression by 61.2% (p = 0.044). Inflammatory factors, including matrix metalloproteinases, cyclooxygenase 2, and tissue factor also significantly (p<0.05) decreased with CCN3 overexpression in the atherosclerotic mouse model. Additionally, CCN1 and CCN2, which have been reported to be highly expressed in aortic atherosclerotic plaques, were significantly downregulated (p<0.05) by CCN3 overexpression. CONCLUSION: CCN3 overexpression is associated with control of inflammatory processes and reversion of dyslipidemia in the process of atherosclerosis, which implies that CCN3 may be a promising target in the treatment of atherosclerosis.

Oxidized low-density lipoprotein increases the proliferation and migration of human coronary artery smooth muscle cells through the upregulation of osteopontin.

Smooth muscle cell (SMC) proliferation and migration are known to play a critical role in the development of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) is involved in the generation of atherosclerotic lesions. Recent studies have indicated that oxLDL is a well-established risk factor for atherosclerosis that induces vascular smooth muscle cell (VSMC) proliferation and migration; however, the exact mechanisms involved have not been fully elucidated. In this study, the proliferation of human coronary artery smooth muscle cells (HCASMCs) was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell migration was determined by Transwell assay. Osteopontin (OPN), matrix metaloproteinase-9 (MMP-9) and αvß3 integrin expression were measured by mRNA and western blot analysis. OPN and MMP-9 knockdown cells were established through transfection with OPN siRNA or MMP-9 siRNA, respectively. Our results revealed that oxLDL makredly promoted HCASMC proliferation and migration in a dose-dependent manner. Further experiments demonstrated that oxLDL upregulated the expression of OPN and oxLDL. Cell proliferation and migration were markedly reduced following the knockdown of the OPN gene in the HCASMCs. We then found that treatment with oxLDL induced a concentration-dependent increase in MMP-9 mRNA and protein levels in the HCASMCs. These effects were partially abrogated by silencing OPN expression or blocking the αvß3 integrin pathway. Moreover, cells treated with MMP-9 siRNA or αvß3 antibody showed lower proliferation and migration rates. This study provides direct in vitro evidence that the exposure of HCASMCs to oxLDL induces the activation of OPN, leading to higher protein levels of MMP-9, and to an increased proliferation and migration of HCASMCs.

Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway.

Ion channels have been suggested to be important in the development and progression of tumors, however, chloride channels have rarely been analyzed in tumorigenesis. More recently, transmembrane protein with unknown function 16A (TMEM16A), hypothesized to be a candidate calcium­activated Cl­ channel, has been found to be overexpressed in a number of tumor types. Although several studies have implicated the overexpression of TMEM16A in certain tumor types, the exact role of TMEM16A in gliomas and the underlying mechanisms in tumorigenesis, remain poorly understood. In the present study, the role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed. TMEM16A was highly abundant in various grades of gliomas and cultured glioma cells. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion. Furthermore, nuclear factor­κB (NF­κB) was activated by overexpression of TMEM16A. In addition, TMEM16A regulated the expression of NF­κB­mediated genes, including cyclin D1, cyclin E and c­myc, involved in cell proliferation, and matrix metalloproteinases (MMPs)­2 and MMP­9, which are associated with the migration and invasion of glioma cells. Collectively, results of the present study provide evidence for the involvement of TMEM16A in gliomas and the potential mechanism through which TMEM16A promotes glioma formation.

Serum S100A12 concentrations are correlated with angiographic coronary lesion complexity in patients with coronary artery disease.

The neutrophil activation marker S100A12 is an important pro-inflammatory cytokine and a potential biomarker for a range of inflammatory diseases. This study aims to investigate whether serum S100A12 concentrations are associated with angiographic coronary lesion complexity in patients with coronary artery disease (CAD). We enrolled 240 CAD and 68 healthy controls. Coronary lesion complexity was assessed by coronary angiography (CAG). Serum S100A12 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). We demonstrated that serum S100A12 concentrations were independently associated with the presence of complex lesion in patients with stable angina pectoris (SAP) (Odds ratio 1.02, 95% CI 1.01-1.04; p < 0.01). In addition, among patients with acute coronary syndrome (ACS) who had significantly higher serum S100A12 concentrations than SAP patients (140.8 [interval 109.4-208.6] vs. 120.8 [interval 96.1-145.9] µg/L, respectively, p < 0.01), those with multi-complex lesions had significantly higher serum S100A12 concentrations than those with no or one complex lesion (156.3 [interval 116.2-247.4] vs. 129.2 [interval 99.8-165.2] µg/L, respectively, p < 0.01). These findings suggest that S100A12 in serum might be a potential biomarker for providing valuable information regarding coronary plaque vulnerability in patients with CAD.

GABAB receptors resist acute desensitization in both postsynaptic and presynaptic compartments of periaqueductal gray neurons.

The ventrolateral midbrain periaqueductal gray (PAG) neurons have been intensively studied because of their pivotal role in the descending pain modulation system. Activation of GABAB receptors, one type of inhibitory G-protein-coupled receptors (GPCRs), in PAG neurons results in both presynaptic and postsynaptic inhibition. Acute desensitization is defined as rapid attenuation of receptor-mediated signaling. Recent studies report that multiple inhibitory GPCRs, including GABAB receptors, resist acute desensitization in the presynaptic but not postsynaptic compartments of certain neurons in mammal brains. In the present study, employing whole-cell voltage-clamp recordings on acute PAG slices from adult rats, we found that GABAB receptors resist acute desensitization to prolonged administration of baclofen (GABAB receptor agonist) in both presynaptic and postsynaptic compartments. The desensitization resistance of postsynaptic GABAB receptors was independent of presynaptic alteration and vice versa. The GABAB receptor-mediated inhibition at inhibitory presynaptic terminals also showed no desensitization. The results suggest that GABAB receptor-mediated inhibition remains functional in both postsynaptic and presynaptic compartments to sustained agonist administration in rat PAG neurons.

Association of the polymorphism of DR4 with the risk and severity of lumbar disc degeneration in the Chinese Han population.

OBJECTIVE: Death receptor 4 (DR4), an apoptosis-associated gene, plays an important role in the pathophysiology of lumbar disc degeneration (LDD). The present study aimed to determine whether the C626G polymorphism (rs4871857) of the DR4 gene is associated with the risk and severity of LDD in the Chinese Han population. METHODS: A total of 296 patients with LDD and 208 healthy controls were enrolled in this study. The grade of disc degeneration was determined according to Schneiderman's classification for MRI. The C626G polymorphism of DR4 was genotyped using polymerase chain reaction and the restriction fragment length polymorphism method. RESULTS: The genotype frequency of the C626G polymorphism was in agreement with the Hardy-Weinberg equilibrium (p = 0.194). The frequencies of the 626CG and GG genotypes were higher among LDD patients compared with normal controls; however, the differences were not significant. Patients with LDD showed significantly higher frequencies of the G allele than normal controls (p = 0.023). Unconditional logistic regression analysis revealed that the G allele was significantly associated with an increased risk of LDD compared with the C allele (p = 0.025; OR 1.958; 95% CI 1.087-3.526). However, no association was found between the different genotypes and the risk of LDD. In addition, the 626CG and GG genotypes, as well as the G allele were associated with higher degenerative grades of LDD compared with the CC genotype and the C allele, respectively (p = 0.005 and p < 0.001, respectively). CONCLUSION: The C626G polymorphism of DR4 may be associated with the risk and severity of LDD in the Chinese Han population.

Tenascin-C produced by oxidized LDL-stimulated macrophages increases foam cell formation through Toll-like receptor-4.

Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immunity are involved. Although there have been major advances in the involvement of toll-like receptor 4 (TLR4) and CD36 in the initiation and development of this disease, detailed mechanisms remain unknown. Here, we show that tenascin-C (TN-C) can stimulate foam cell formation and this can be inhibited by a TLR4-blocking antibody or CD36 gene silencing. Our results identify TN-C-TLR4 activation as a common molecular mechanism in oxLDL-stimulated foam cell formation and atherosclerosis. In addition, CD36 is the major scavenger receptor responsible for the TN-C-mediated foam cell formation. Taken together, we have identified that TNC produced by oxLDL-stimulated macrophages increases foam cell formation through TLR4 and scavenger receptor CD36.

Postprocedural serum sLOX-1 levels are associated with coronary in-stent restenosis in patients with stable coronary artery disease.

OBJECTIVES: We tested whether serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) levels are able to predict in-stent restenosis (ISR) after successful primary percutaneous coronary intervention (PCI). METHODS: Preprocedural and postprocedural serum sLOX-1 levels were measured in 210 consecutive patients with stable coronary artery disease who underwent successful primary PCI for de novo lesions. The patients were grouped as ISR and non-ISR based on angiographic follow-up results. RESULTS: PCI significantly increased serum sLOX-1 levels both in patients with [0.85 (range: 0.63-0.98) vs. 0.39 (range: 0.27-0.54) ng/ml, P < 0.01] or without ISR [0.45 (range: 0.36-0.84) vs. 0.32 (range: 0.28-0.62) ng/ml, P < 0.01]. Postprocedural serum sLOX-1 levels were higher in patients with ISR than those without ISR [0.85 (range: 0.63-0.98) vs. 0.45 (range: 0.36-0.84) ng/ml, P < 0.01]. High postprocedural serum sLOX-1 levels served as independent predictors of ISR (odds ratio: 3.040, 95% confidence interval: 1.359-6.802, P < 0.01). Furthermore, postprocedural serum sLOX-1 levels were correlated with late lumen loss of the stented lesions (ρ = 0.36, P < 0.01). CONCLUSION: Postprocedural serum sLOX-1 levels are significantly associated with the risk of ISR and the severity of lumen loss in patients with stable coronary artery disease undergoing primary PCI. These results suggested that postprocedural serum sLOX-1 levels might be useful for the detection and risk assessment of ISR after PCI.

Serum sLOX-1 levels are associated with the presence and severity of angiographic coronary artery disease in patients with metabolic syndrome.

PURPOSE: Patients with metabolic syndrome are at high-risk for development of atherosclerosis and cardiovascular events. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1(sLOX-1) is associated with coronary artery disease (CAD) and metabolic disorders. We sought to assess whether serum sLOX-1 levels are correlated with the presence and severity of CAD in patients with metabolic syndrome (MetS) undergoing coronary angiography. METHODS: Serum sLOX-1 levels were measured in 112 consecutive patients with MetS, undergoing coronary angiography for the evaluation of CAD. The severity of CAD was assessed by angiographic Gensini score system. RESULTS: Serum sLOX-1 levels were significantly higher in MetS patients with CAD (n=69) than in those without CAD (n=43) (0.925 [range 0.137 to 1.432] ng/ml vs. 0.207 [range 0.063 to 0.774] ng/ml, P < 0.01). Multivariate logistic regression analysis revealed that serum sLOX-1 level was independently associated with the presence of CAD (odds ratio 2.489, 95% confidence interval 1.290-4.802; P < 0.01). Serum sLOX-1 levels were positively correlated with the Gensini score (ρ: 0.394, P < 0.01) after adjusting for other clinical characteristics. CONCLUSIONS: High sLOX-1 levels are associated with the presence and severity of CAD in patients with MetS. The measurement of serum sLOX-1may be potentially useful in predicting the presence and severity of CAD in patients with MetS.