Gas chromatography-mass spectrometry pilot study to identify volatile organic compound biomarkers of childhood obesity with dyslipidemia in exhaled breath.

Objectives: Childhood obesity affects multiple organs in the body and is associated with both significant morbidity and ultimately premature mortality. Childhood obesity, especially dyslipidemia, can lead to early atherosclerosis and premature cardiovascular disease (CVD) in adulthood. The detection of exhaled volatile organic compounds (VOCs) in the breath offers the opportunity for the discovery of novel disease-specific biomarkers. This study aimed to identify VOCs that correlate with childhood obesity accompanied by dyslipidemia. Methods: A total of 82 overweight or obese children between the ages of 8 and 12 years were recruited from the exercise on obesity adolescents in Peking (EXCITING) study (NCT04984005). The breath VOCs of the participants were measured by gas chromatography-mass spectrometry (GC-MS). The classification was performed using principal component analysis (PCA) of the relative abundance of VOCs. The difference between the obese and overweight groups with or without dyslipidemia was analyzed. Results: Among the 82 children, 25 were overweight, of whom 10 had dyslipidemia. The other 57 children were obese, and 17 of them had dyslipidemia. Obese children with dyslipidemia had higher triglycerides and elevated non-high-density lipoprotein-cholesterol compared to overweight children without dyslipidemia. We confirmed 13 compounds based on database well matches (average score > 80) for mass spectra and refractive index. These 13 VOCs were grouped into three chemical functional groups: saturated hydrocarbons, aromatic hydrocarbons and unsaturated aldehydes. For obese children with dyslipidemia, the PCA scatter plot of the three chemical groups was obviously separated from the other groups. Some of the candidates, including heptadecane, naphthalene, and cis-6-nonnenol, were significantly higher in obese children with dyslipidemia than in overweight groups with or without dyslipidemia. Conclusion: A suite of VOCs from three chemical function groups, saturated hydrocarbons, aromatic hydrocarbons, and unsaturated aldehydes, were separated in the obese children with dyslipidemia. Heptadecane, naphthalene, and cis-6-nonenol were significantly elevated in obese children with dyslipidemia. Our findings underscore the potential value of the candidate VOCs for future risk categorization.

Exercise training attenuates angiotensin II-induced cardiac fibrosis by reducing POU2F1 expression.

BACKGROUND: Exercise training protects against heart failure. However, the mechanism underlying the protective effect of exercise training on angiotensin II (Ang II)-induced cardiac fibrosis remains unclear. METHODS: An exercise model involving C57BL/6N mice and 6 weeks of treadmill training was used. Ang II (1.44 mg/kg/day) was administered to induce cardiac fibrosis. RNA sequencing and bioinformatic analysis were used to identify the key factors mediating the effects of exercise training on cardiac fibrosis. Primary adult mouse cardiac fibroblasts (CFs) were used in vitro. Adeno-associated virus serotype 9 was used to overexpress POU domain, class 2, transcription factor 1 (POU2F1) in vivo. RESULTS: Exercise training attenuated Ang II-induced cardiac fibrosis and reversed 39 gene expression changes. The transcription factor regulating the largest number of these genes was POU2F1. Compared to controls, POU2F1 was shown to be significantly upregulated by Ang II, which is itself reduced by exercise training. In vivo, POU2F1 overexpression nullified the benefits of exercise training on cardiac fibrosis. In CFs, POU2F1 promoted cardiac fibrosis. CCAAT enhancer-binding protein ß (C/EBPß) was predicted to be the transcription factor of POU2F1 and verified using a dual-luciferase reporter assay. In vivo, exercise training activated AMP-activated protein kinase (AMPK) and alleviated the increase in C/EBPß induced by Ang II. In CFs, AMPK agonist inhibited the increase in C/EBPß and POU2F1 induced by Ang II, whereas AMPK inhibitor reversed this effect. CONCLUSION: Exercise training attenuates Ang II-induced cardiac fibrosis by reducing POU2F1. Exercise training inhibits POU2F1 by activating AMPK, which is followed by the downregulation of C/EBPß, the transcription factor of POU2F1.

The adverse inflammatory response of tobacco smoking in COVID-19 patients: biomarkers from proteomics and metabolomics.

Whether tobacco smoking affects the occurrence and development of coronavirus disease 2019 (COVID-19) is still a controversial issue, and potential biomarkers to predict the adverse outcomes of smoking in the progression of COVID-19 patients have not yet been elucidated. To further uncover their linkage and explore the effective biomarkers, three proteomics and metabolomics databases (i.e. smoking status, COVID-19 status, and basic information of population) from human serum proteomic and metabolomic levels were established by literature search. Bioinformatics analysis was then performed to analyze the interactions of proteins or metabolites among the above three databases and their biological effects. Potential confounding factors (age, body mass index (BMI), and gender) were controlled to improve the reliability. The obtained data indicated that smoking may increase the relative risk of conversion from non-severe to severe COVID-19 patients by inducing the dysfunctional immune response. Seven interacting proteins (C8A, LBP, FCN2, CRP, SAA1, SAA2, and VTN) were found to promote the deterioration of COVID-19 by stimulating the complement pathway and macrophage phagocytosis as well as inhibiting the associated negative regulatory pathways, which can be biomarkers to reflect and predict adverse outcomes in smoking COVID-19 patients. Three crucial pathways related to immunity and inflammation, including tryptophan, arginine, and glycerophospholipid metabolism, were considered to affect the effect of smoking on the adverse outcomes of COVID-19 patients. Our study provides novel evidence and corresponding biomarkers as potential predictors of severe disease progression in smoking COVID-19 patients, which is of great significance for preventing further deterioration in these patients.

The R93C Variant of PCSK9 Reduces the Risk of Premature MI in a Chinese Han Population.

Background: Dyslipidemia is a common risk factor for premature myocardial infarction (PMI). Our previous work has shown that single-nucleotide polymorphisms (SNPs) of LDLR, APOB, and PCSK9 are associated with dyslipidemia, but how these SNPs correlate with risk for PMI is unknown. Objective: This study aims to evaluate the association between SNPs of LDLR, APOB, and PCSK9 and risk of PMI in Chinese Han population. Methods: Two cohorts were established. In Cohort 1 (413 in the PMI group and 1,239 in the control group), SNPs of APOB, LDLR, and PCSK9 with minor allele frequency (MAF) > 1%, which has been shown to impact the risk of PMI in a Chinese Han population, were thoroughly examined, and gene-environment interactions were analyzed. A model for PMI risk prediction was developed in Cohort 1 and externally validated in Cohort 2 (577 in the PMI group and 270 in the control group). Results: The distribution of the T allele at the PCSK9 R93C variant (rs151193009, C > T) was lower in the PMI group than that in the control group (PMI vs. Control in Cohort 1, 0.8% vs. 2.3%, P adjust < 0.05; in Cohort 2, 1.0% vs. 2.4%, P adjust < 0.05). The T allele at PCSK9 R93C variant (rs151193009, C > T) reduced the risk of PMI by ∼60% regardless of adjusting for confounding factors (in Cohort 1, adjusted odds ratio (OR) 0.354, 95% confidence interval (CI) 0.139-0.900, p = 0.029; in Cohort 2, adjusted OR 0.394, 95% CI 0.157-0.987, p = 0.047). No gene-environment interactions were observed between the R93C variant and diabetes/hypertension/smoking in PMI occurrence in this Chinese Han population. Our model showed good performance in predicting the risk of PMI in Cohort 1 (AUC 0.839, 95% CI 0.815-0.862, p < 0.001) and in an external cohort (AUC 0.840, 95% CI 0.810-0.871, p < 0.001). Conclusions: The PCSK9 R93C variant was associated with significantly reduced risk of PMI in the Chinese Han population, and the model we developed performed well in predicting PMI risk in this Chinese Han population.

Surface charge-dependent mitochondrial response to similar intracellular nanoparticle contents at sublethal dosages.

BACKGROUND: Considering the inevitability for humans to be frequently exposed to nanoparticles (NPs), understanding the biosafety of NPs is important for rational usage. As an important part of the innate immune system, macrophages are widely distributed in vital tissues and are also a dominant cell type that engulfs particles. Mitochondria are one of the most sensitive organelles when macrophages are exposed to NPs. However, previous studies have mainly reported the mitochondrial response upon high-dose NP treatment. Herein, with gold nanoparticles (AuNPs) as a model, we investigated the mitochondrial alterations induced by NPs at a sublethal concentration. RESULTS: At a similar internal exposure dose, different AuNPs showed distinct degrees of effects on mitochondrial alterations, including reduced tubular mitochondria, damaged mitochondria, increased reactive oxygen species, and decreased adenosine triphosphate. Cluster analysis, two-way ANOVA, and multiple linear regression suggested that the surface properties of AuNPs were the dominant determinants of the mitochondrial response. Based on the correlation analysis, the mitochondrial response was increased with the change in zeta potential from negative to positive. The alterations in mitochondrial respiratory chain proteins indicated that complex V was an indicator of the mitochondrial response to low-dose NPs. CONCLUSION: Our current study suggests potential hazards of modified AuNPs on mitochondria even under sublethal dose, indicates the possibility of surface modification in biocompatibility improvement, and provides a new way to better evaluation of nanomaterials biosafety.

An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population.

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (ß = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

Ring finger protein 152-dependent degradation of TSPAN12 suppresses hepatocellular carcinoma progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear. METHODS: Transcriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152. RESULTS: We found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression. CONCLUSION: Collectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.

Neuregulin-1 alleviate oxidative stress and mitigate inflammation by suppressing NOX4 and NLRP3/caspase-1 in myocardial ischaemia-reperfusion injury.

Neuregulin-1 (NRG-1) is reported to be cardioprotective through the extracellular-regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia-reperfusion injury (MIRI). NOX4-induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG-1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase-1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC-Evans blue staining. Immunohistochemical staining, real-time quantitative PCR (RT-qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase-1 and IL-1ß .The IS in the NRG-1 (3 µg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG-1 decreased 4HNE and NOX4. The RT-qPCR and Western blot analyses revealed that NRG-1 mitigated the IR-induced up-regulation of NOX4 and ROS production. Compared with the IR group, the NRG-1 group exhibited a higher level of P-ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up-regulated the expression of NOX4, NLRP3, caspase-1 and IL-1ß, which exacerbated oxidative stress and inflammation. In conclusion, NRG-1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase-1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.

Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway.

BACKGROUND: The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP). METHODS: We used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 µg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis. RESULTS: We found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1. CONCLUSION: In conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury.

Plasma Catestatin: A Useful Biomarker for Coronary Collateral Development with Chronic Myocardial Ischemia.

BACKGROUNDS: Catestatin is an endogenous multifunctional neuroendocrinepeptide. Recently, catestatin was discovered as a novel angiogenic cytokine. The study was to investigate the associations between endogenous catestatin and coronary collateral development among the patients with chronic myocardial ischemia. METHODS: Thirty-eight patients with coronary artery chronic total occlusions (CTO) (CTO group) and 38 patients with normal coronary arteries (normal group) were enrolled in the series. Among the patients with CTO, coronary collateral development was graded according to the Rentrop score method. Rentrop score 0-1 collateral development was regarded as poor collateral group and 2-3 collateral development was regarded as good collateral group. Plasma catestatin level and vascular endothelial growth factor (VEGF) were measured by ELISA kits. RESULTS: The plasma catestatin levels in CTO group were significantly higher than that in normal group (1.97±1.01 vs 1.36±0.97ng/ml, p = 0.009). In the CTO group, the patients with good collateral development had significantly higher catestatin and VEGF levels than those with poor collateral development (2.36±0.73 vs 1.61±1.12 ng/ml, p = 0.018; 425.23±140.10 vs 238.48±101.00pg/mL, p<0.001). There is a positive correlation between plasma catestatin levels and Rentrop scores (r = 0.40, p = 0.013) among the patients with CTO. However, there is no correlations between plasma catestatin levels and VEGF (r = -0.06, p = 0.744). In the multiple linear regression models, plasma catestatin level was one of the independent factors of coronary collateral development after adjustment for confounders. CONCLUSIONS: Plasma catestatin was associated with coronary collateral developments. It may be a useful biomarker for coronary collateral development and potential target for therapeutic angiogenesis in patients with CTO.

Long-term outcome following thulium vaporesection of the prostate.

BACKGROUND: The continuous wave 2-µm Thulium Laser has been introduced as potential technology with both high efficiency and safe practice; although little data have been shown regarding the long-term outcomes. OBJECTIVE: To analyze the long-term outcomes after thulium vaporesection of the prostate (ThuVaRP). METHODS: ThuVaRP was performed using the continuous wave, 2-µm Thulium: YAG laser at 70 W. The perioperative and post-operative follow-up data were analyzed. RESULTS: The average age at surgery was 71.5 (range 55-94 years). The median prostate size was 60.1 g (range 36.3-109.8 g). A median operation time was noted at 44.8 ± 6.5 minutes, while the median catheterization time was 3.5 ± 0.5 days. In regards to hospital stay, most patients had an average duration of 5.5 ± 1.5 days. Minor complications requiring non-interventional treatment happened in 237 (36.24%) of 654 patients, while major complications requiring re-interventions occurred in one patient (0.15%). During a 60-month follow-up, bladder neck fibrosis occurred in 1.22% of the patients. A BPH recurrence happened in 17 (2.60%) patients, of which 14 patients (2.14%) received a second surgery. In comparison to the pre-operative baseline, the patients Qmax, PVR volume, IPSS, and Qol scores all improved significantly (P < 0.01) at time of discharge. This continued into the post-operative follow-up visits (3-6-12-18-14-26-48-60 months). CONCLUSIONS: ThuVaRP is both an effective and safe treatment procedure for symptomatic BPO (with a low occurrence of complications). Lasers Surg. Med. 48:505-510, 2016. © 2016 Wiley Periodicals, Inc.

Soluble CD40 ligand is associated with angiographic severity of coronary artery disease in patients with acute coronary syndrome.

BACKGROUND: Recently, studies have disclosed soluble CD40 ligand (sCD40L) during atherosclerosis development and plaque destabilization. The objective of the present study was to test the hypothesis that sCD40L levels are higher in acute coronary syndrome (ACS) patients with a greater extent of angiographic coronary involvement. METHODS: This cross-sectional study examined ACS patients who underwent coronary angiography by measuring their sCD40L levels. In order to estimate the serum levels of sCD40L, 10 ml of peripheral venous blood was drawn within 24 hours of admission. sCD40L levels were measured using an enzyme-linked immunosorbent assay (ELISA, RapidBio, West Hills, CA, USA). Demographic data, presence of concomitant diseases, ACS characteristics, and angiographic findings were evaluated. A review of medical records and patient interviews were conducted to assess coronary risk factors. And the severity of coronary artery disease was evaluated using the Gensini score index. RESULTS: Two hundred and eighty-nine patients were included in the study, of whom 186 were male, with an average age of 64.1 ± 10.0 years. Median sCD40L levels were 1.7 ng/ml (0.3-7.3 ng/ml) and Gensini scores were 50 (0-228). After adjusting for demographic variables and cardiovascular risk factors, the Gensini score was associated with the natural logarithm of the sCD40L level (Coefficient b = 0.002, 95% CI 0.000-0.003, P = 0.029). CONCLUSION: sCD40L levels were independently associated with angiographic severity of coronary artery disease in patients with ACS.

[Clopidogrel resistance of patients with coronary artery disease and its correlation with platelet count and mean platelet volume].

OBJECTIVE: To explore the association between clopidogrel resistance (CR) as assessed by whole blood electrical impedance aggregometry (EIA) and platelet parameters. METHODS: The prospective study comprised 152 patients with coronary artery disease (CAD) on the therapy of clopidogrel. EIA employed adenosine diphosphate (ADP) as an inductor to measure platelet aggregation. CR was defined by spontaneous aggregation (electrical impedance ≥ 10 Ω). The subjects were divided into 2 groups of CR and clopidogrel sensitive (CS). Platelet parameters were measured by routine blood test. And their clinical data and outcomes were analyzed. RESULTS: The prevalence of CR was 10.5% (n = 16). The ratio of patients with diabetes in CR group was higher than that in CS group (7/16 vs 29/136, P = 0.046). Platelet counts and mean platelet volume (MPV) were also higher in CR group than those in CS group ((241 ± 58) ×10(9)/L vs (185 ± 56)×10(9)/L, (8.0 ± 0.8) fl vs (7.4 ± 0.9) fl, both P < 0.05). Logistic regression indicated each 10×10(9)/L increase in platelet and each 1 fl increase in MVP were associated with 0.376 and 1.015 folds increase in CR onset respectively (OR = 1.376, 95%CI 1.097 - 1.725, P = 0.006;OR = 2.015, 95%CI 1.148 - 3.537, P = 0.015). The patients with CR had more cardiovascular events during an average follow-up of 53 months (6/16 vs 23/136, P = 0.047). CONCLUSIONS: CAD patients with CR had higher incidence of cardiovascular events. Increased platelet counts and MPV levels are independent predictors for CR in CAD patients.

[Correlation between antiplatelet resistance and recurrent cardiac ischemic events of patients with acute myocardial infarction].

OBJECTIVE: To evaluate the predictive value of antiplatelet resistance assessed by whole blood electronic impedance aggregometry (EIA) for the risk of recurrent cardiac ischemic events in patients with acute myocardial infarction (AMI) who underwent coronary stenting. METHODS: We enrolled 109 patients with AMI, 72 (66.1%) men and 37 (33.9%) women with mean age (63 ± 12) years, who were treated with aspirin and clopidogrel daily after coronary stenting. EIA used arachidonic acid (AA) and adenosine diphosphate (ADP) as inductors to measure platelet aggregation inhibited by aspirin and clopidogrel respectively. The subjects were divided into four groups: pure aspirin resistant group (AR, electrical impedance > 0 Ω), pure clopidogrel resistant group (CR, electrical impedance ≥ 10 Ω), dual resistant group (DR) and dual sensitive group (DS). The primary outcomes were recurrent cardiac ischemic events during the 12-month follow-up. RESULTS: Antiplatelet resistance occurred more often in patients with type 2 diabetes (P = 0.027). The platelet counts (PLT) were higher in antiplatelet resistant groups than DS group (P = 0.013). During the 12-month follow-up, the antiplatelet resistant patients had a higher incidence of recurrent cardiac ischemic events and stent thrombosis (ST) than the patients without (12.5%, 10.0%, 50.0% vs 3.8%, P = 0.036; 6.3%, 10.0%, 50.0% vs 1.3%, P = 0.000; respectively). Binary Logistic regression indicated that dual resistance remained an independent predicator of recurrence cardiac ischemic events and ST (OR 5.99, 95%CI 1.05 - 34.34, P = 0.045; OR 6.36, 95%CI 1.13 - 35.78, P = 0.036; respectively). CONCLUSIONS: As a physiological assessment of platelet reactivity, EIA is a convenient and accurate option for measuring aspirin resistance. Antiplatelet resistance assessed by EIA is paralleled to clinical events. Dual resistance is an independent predicator for ST and recurrence cardiac ischemic events in patients with AMI.

Mitofusin 2 inhibits angiotensin II-induced myocardial hypertrophy.

BACKGROUND AND OBJECTIVES: Myocardial hypertrophy is a common clinical finding leading to heart failure and sudden death. Mitofusin 2 (Mfn2), a hyperplasia suppressor protein, is downregulated in hypertrophic heart. This study examined the role of Mfn2 in myocardial hypertrophy and its potential signal pathway. METHODS AND RESULTS: In in vitro studies, neonatal cardiac myocytes were isolated and cultured. Incubation of cultured cardiomycytes with angiotensin II (Ang II) inhibited gene expression of Mfn2; induced cell hypertrophy and protein synthesis; and activated protein kinase Akt. Pretreatment of cells with AdMfn2-a replication-deficient adenoviral vector encoding rat Mfn2 gene-upregulated Mfn2 expression and subsequently attenuated Ang II-induced cell hypertrophy; protein synthesis; and Akt activation. In in vivo studies, direct gene delivery of AdMfn2 into myocardium decreased the infusion of Ang II-induced atrial natriuretic factor (ANF, a hypertrophic marker) expression and cardiomyocyte cross-sectional area. Consistently, upregulation of Mfn2 in myocardium decreased the thicknesses of anterior and posterior walls of left ventricle (LV) and the ratio of LV mass/body weight in Ang II-treated rats. Of note, AdGFP (control for AdMfn2) did not affect the effects of Ang II in vitro or in vivo. CONCLUSIONS: Upregulation of Mfn2 inhibits Ang II-induced myocardial hypertrophy. In this process, inhibition of Akt activation seems to play a significant role. These findings indicate Mfn2 is a critical protein in modulating myocyte hypertrophy.

Growth differentiation factor 15 in different stages of heart failure: potential screening implications.

Identification of individuals in the early stage of heart failure (HF) may allow earlier initiation of disease-modifying treatment. We evaluated concentrations of the growth differentiation factor (GDF)-15 at different stages and its potential screening value in 208 subjects. Plasma GDF-15 was measured by using an enzyme-linked immunosorbent assay. GDF-15 was positively correlated with the stages of HF (r=0.804, p<0.001). In distinguishing patients with stage B HF, the area under the curve was 0.873 (p<0.001). These findings indicate that GDF-15 concentration was elevated with the progressing stages of HF and might have potential screening implications for stage B HF.

[Adhesion between monocytes and vascular smooth muscle cells induced by integrin beta1-mediated platelet-derived growth factor].

OBJECTIVE: To investigate the effects of platelet-derived growth factor (PDGF)-BB on the vascular smooth muscle cell (VSMC)-monocyte interaction and the mechanism thereof. METHODS: Rat aortic VSMC were pretreated with PDGF-BB of the concentrations of 0, 2.5, 5, 10, and 20 ng/ml for 8 hours and then co-incubated with human monocytes of the line THP-1 labeled with PKH26, a cellular membrane fluorescent marker, i.e., to be subjected to binding assay to observe the dose-effect relationship. Other VSMC were co-cultured with PDGF of the concentration of 10 ng/ml for 1, 2, 4, 12, and 24 hours respectively and then interacted with PKH26-abeled THP-1 cells so as to observe the time-response relationship. Monoclonal antibody against integrin beta1 was co-cultured with VSMC for 30 min, and then PKH26-labeled THP-1 cells were added to block the effect of PDGF. After the incubation of THP-1 cells and VSMC, the amount of bound cells was counted using fluorescent phase-contrast microscopy. The effect of PDGF on the expression of integrin beta1 was detected by Western blotting. RESULTS: The amounts of THP-1 cells bound to VSMC pretreated with PDGF of the concentrations of 2.5, 5, 10, and 20 ng/ml respectively were 1.1, 2.1, 3.1, and 4.4 times that of the untreated cells. Incubated with 10 ng/ml PDGF for 0-18 h, the adhesion rate between the VSMC and THP-1 cells increased time-1dependently. After the blocking by the antibody against integrin beta1, the adhesion rate between the VSMC and THP-1 cells decreased from (25.4+/-11.4)% to (9.2+/-4.1)% (P<0.01). Western blotting showed that the level of integrin beta1 of the VSMC treated by 10 ng/ml PDGF increased since 4 h after the treatment, peaked 8 h later, and then decreased gradually. CONCLUSION: PDGF-BB can induce the binding of monocytes to VSMC via the integrin-beta1 signaling pathway. The effect may therefore facilitate the progression of atherosclerosis by augmenting the VSMC-monocyte adhesive interaction.