Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.

BACKGROUND: The nuclear receptor Rev-erbα/ß, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. METHODS: We generated mouse lines with cardiac-specific Rev-erbα/ß knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) analyses, and performed dietary and pharmacological rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. RESULTS: KO mice display progressive dilated cardiomyopathy and lethal heart failure. Inducible ablation of Rev-erbα/ß in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, in particular, in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, in particular, in the dark cycle. Increasing dietary lipid or sugar supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acid availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorate cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with dilated cardiomyopathy. CONCLUSIONS: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.

Functional characterization of GATA6 genetic variants associated with mild congenital heart defects.

Damaging GATA6 variants can cause moderate congenital heart defects. With the application of next-generation sequencing approaches, various novel GATA6 variants with unknown significance have been identified from a broad spectrum of congenital heart defects. However, functional assessment for distinct GATA6 variants from different severity of congenital heart defects, especially from mild defects, is lacking, which hinders our understanding of the genotype-phenotype correlations and underlying mechanisms. Here, we assessed the functional consequences of nine rare GATA6 variants, which had been implicated as the most significant variants associated with mild congenital heart defects using the largest case and control cohort. We examined the effects of these variants on subcellular localization, transcriptional activity, and protein interactions in 293T or AC16 cells and their ability to rescue heart malformation in gata6 zebrafish mutant. We found that two of these nine variants, Q120X and S424I, significantly decreased transcriptional activity. Additionally, Q120X altered subcellular localization. Consistent with the in vitro results, the in vivo results showed that Q120X and S424I lost their potency to rescue ventricular malformation in gata6 -/- embryos. The results indicated that Q120X and S424I are pathogenic in mild congenital heart defects. Further, the inconsistence of severely impaired Q120X function and mild CHDs phenotype suggested the complexity of the genotype-phenotype correlation between the GATA6 variant and heart phenotype, which may help to inform prenatal genetic counseling and pre-implantation genotyping for congenital heart defects.

Protective Roles of Xijiao Dihuang Tang on Coronary Artery Injury in Kawasaki Disease.

PURPOSE: Xijiao Dihuang Tang (XJDHT) is a classical formula of traditional Chinese medicine constituted of Cornu Bubali, Rehmannia glutinosa (Gaertn.) DC., Paeonia lactiflora Pall., and Paeonia suffruticosa Andrews. It was first mentioned in the medical classic "Beiji Qianjin Yaofang" written by Simiao Sun in Tang Dynasty. It shows very strong antipyretic and anticoagulant effects and has been clinically applied to treat various type of blood loss, purple and black spots, heat stroke, and glossitis. Kawasaki disease (KD) is considered as a kind of acute febrile illness in children with systemic vasculitis as the main lesions. The aim of this research is to clarify whether XJDHT can play a protective role in KD. METHODS: A mouse model of Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis and a KD cell model with tumor necrosis factor (TNF)-α induction were employed to investigate the potential effect and mechanism of XJDHT on coronary artery injury in KD. RESULTS: Data showed that XJDHT remarkably alleviated the coronary artery injury of KD mice, as evidenced by reduced inflammation and downregulated expression of pro-inflammatory cytokines interleukin (IL)-1ß and TNF-α. In vitro investigation showed that XJDHT could promote cell proliferation, inhibit cell apoptosis, and improve mitochondrial functions. Subsequent studies demonstrated that XJDHT rescued endothelial cell injury by PI3K/Akt-NFκB signaling pathway. Component analysis of XJDHT detected thirty-eight chemically active ingredients, including paeoniflorin, albiflorin, and paeoniflorigenone, which in in vitro experiments exhibited significant rescue effects on TNF-α-mediated endothelial cell injury. CONCLUSION: Our findings demonstrated that XJDHT mitigated coronary artery injury of KD through suppressing endothelial cell damage via PI3K/Akt-NFκB signaling.

Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling.

Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 µM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor ß-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.

Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα.

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.

Overweight, obesity and coronary artery lesions among Kawasaki disease patients.

BACKGROUND AND AIMS: Overweight is associated with increased cardiovascular disease in general populations. However, a similar relationship among Kawasaki Disease (KD) patients was unclear. The study aimed to investigate the relation between weight-for-height and coronary artery lesions (CAL) among KD patients, and whether laboratory indices modified this relation. METHODS AND RESULTS: All consecutive KD patients from January 2009 to December 2014 in a city in China were reviewed, and classified into overweight/obese and control groups. All patients were followed to assess the occurrence of CAL by echocardiography for two months from disease onset. The independent effect of overweight/obesity on CAL was evaluated after adjustment for confounders. The interaction effect between overweight and laboratory indices was examined. The prevalence of overweight/obesity among KD patients was 18.5% (95%CI: 16.0%, 21.0%). The proportion of male patients and the proportion of non-standard IVIG treatment were significantly higher in overweight/obese children in comparison with their counterparts. Overweight/obesity was associated with increased odds of total CAL (aOR = 1.69, 95%CI: 1.16, 2.45) and also increased odds of CAL after treatment (aOR = 1.96, 95%CI: 1.09, 3.51); after adjustment for age, gender, KD type, change of medical departments, number of days before admission, treatment regimen and laboratory index. Similar results were found using stratification analysis. In addition, patients at risk of overweight were also associated with significantly increased risk of CAL. There was interaction between weight-for-height and platelet, WBC, and albumin. CONCLUSIONS: Overweight/obesity may be an independent risk factor for CAL among KD patients. Some laboratory indicators may modify this association.

Exosomes derived from umbilical cord mesenchymal stem cells alleviate viral myocarditis through activating AMPK/mTOR-mediated autophagy flux pathway.

Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-exosomes) have been implicated as a novel therapeutic approach for tissue injury repair and regeneration, but the effects of hucMSC-exosomes on coxsackievirus B3 (CVB3)-induced myocarditis remain unknown. The object of the present study is to investigate whether hucMSC-exosomes have therapeutic effects on CVB3-induced myocarditis (VMC). HucMSC-exosomes were identified using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blot. The purified hucMSC-exosomes tagged with PKH26 were tail intravenously injected into VMC model mice in vivo and used to administrate CVB3-infected human cardiomyocytes (HCMs) in vitro, respectively. The effects of hucMSC-exosomes on myocardial pathology injury, proinflammatory cytokines and cardiac function were evaluated through haematoxylin and eosin (H&E) staining, quantitative polymerase chain reaction (qPCR) and Doppler echocardiography. The anti-apoptosis role and potential mechanism of hucMSC-exosomes were explored using TUNEL staining, flow cytometry, immunohistochemistry, Ad-mRFP-GFP-LC3 transduction and Western blot. In vivo results showed that hucMSC-exosomes (50 µg iv) significantly alleviated myocardium injury, shrank the production of proinflammatory cytokines and improved cardiac function. Moreover, in vitro data showed that hucMSC-exosomes (50 µg/mL) inhibited the apoptosis of CVB3-infected HCM through increasing pAMPK/AMPK ratio and up-regulating autophagy proteins LC3II/I, BECLIN-1 and anti-apoptosis protein BCL-2 as well as decreasing pmTOR/mTOR ratio, promoting the degradation of autophagy flux protein P62 and down-regulating apoptosis protein BAX. In conclusion, hucMSC-exosomes could alleviate CVB3-induced myocarditis via activating AMPK/mTOR-mediated autophagy flux pathway to attenuate cardiomyocyte apoptosis, which will be benefit for MSC-exosome therapy of myocarditis in the future.

Inhibition of TGFß-activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression.

Transforming growth factor ß-activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z-7-oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R-induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R-induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.

The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling.

As a m6A methylation modifier, METTL3 is functionally involved in various biological processes. Nevertheless, the role of METTL3 in osteogenesis is not determined up to date. In the current study, METTL3 is identified as a crucial regulator in the progression of osteogenic differentiation. Loss of METTL3 significantly augments calcium deposition and enhances alkaline phosphatase activity of mesenchymal stem cells, uncovering an inhibitory role of METTL3 in osteogenesis. More importantly, the underlying molecular basis by which METTL3 regulates osteogenesis is illustrated. We find that METTL3 positively regulates expression of MYD88, a critical upstream regulator of NF-κB signaling, by facilitating m6A methylation modification to MYD88-RNA, subsequently inducing the activation of NF-κB which is widely regarded as a repressor of osteogenesis and therefore suppressing osteogenic progression. Moreover, the METTL3-mediated m6A methylation is found to be dynamically reversed by the demethylase ALKBH5. In summary, this study highlights the functional importance of METTL3 in osteogenic differentiation and METTL3 may serve as a promising molecular target in regenerative medicine, as well as in the field of bone tissue engineering.

The long noncoding RNA NR_045363 involves cardiomyocyte apoptosis and cardiac repair via p53 signal pathway.

Long noncoding RNAs (lncRNAs) can participate in various biological behaviors, including regulating cell differentiation, proliferation, and apoptosis. The investigators have previously confirmed that highly conserved lncRNA NR_045363 controls cardiomyocyte (CM) proliferation and cardiac repair. The present study investigates the effects of NR_045363 on CM apoptosis. Seven-day-old mice were subjected to permanent left anterior descending coronary artery ligation (LAD), and the NR_045363 expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of NR_045363 in the MI group significantly exceeded the Sham group during the first week after the operation. The NR_045363 expression was knocked down in primary cultured CMs using an NR_045363-targeting lncRNA Smart silencer, and the apoptosis of CMs was analyzed by terminal-deoxynucleoitidyl transferase mediated nick end labeling and Annexin-V/PI double staining. These present results indicate that the NR_045363 knockdown significantly promoted the apoptosis of CMs. In order to investigate the underlying mechanism, RNA-sequencing (RNA-seq) was performed, and ingenuity pathway analysis (IPA) was used to analyze the RNA-seq results. The RNA-seq data revealed that a total of 2,291 genes were upregulated or downregulated in NR_045363 knockdown CMs, and the IPA analysis indicated that tumor protein 53 (p53) was the upstream regulator. In vivo, the NR_045363 overexpression through the AAV9 system improved the heart function after MI in 7-day-old mice and inhibited the CM apoptosis. These data suggest that NR_045363 is involved in CM apoptosis and that NR_045363 overexpression exerts positive effects on cardiac repair by alleviating CM apoptosis through the inhibition of the p53 pathway.

Association between the miRNA-149 rs2292832 T>C polymorphism and Kawasaki disease susceptibility in a southern Chinese population.

BACKGROUND: Kawasaki disease (KD), which is characterized by vasculitis, is prone to occur in patients under 5 years of age, has an ambiguous etiology, and displays coronary artery lesions as the chief complication. Previous studies have linked miRNA-149 to cancers, and rs2292832 T>C is related to allergic diseases and inflammatory bowel disease, which both show immune system disorders and coronary artery disease. Therefore, we performed a study concentrating on the association between the miRNA-149 rs2292832 T>C polymorphism and KD susceptibility. METHODS: The subjects enrolled were 532 children with KD and 623 controls. We used TaqMan real-time PCR to obtain the genotypes of the rs2292832 T>C polymorphism. RESULTS: Ultimately, no significant association was found between the miRNA-149 rs2292832 T>C polymorphism and KD susceptibility, even in stratification analysis. CONCLUSION: Our results indicated that in southern Chinese patients, the miRNA-149 rs2292832 T>C polymorphism did not affect KD susceptibility, which needs to be further confirmed.

LncRNA NKILA regulates endothelium inflammation by controlling a NF-κB/KLF4 positive feedback loop.

Endothelium inflammation, a key event in vascular pathological process, can lead to endothelial activation and subsequent vascular disorders. Long non-coding RNA NKILA plays an important regulatory role in pro-inflammatory response. However, the underlying molecular basis by which NKILA regulates endothelial inflammation is poorly understood. In this study, we identify NKILA as a critical repressor to protect the endothelium from inflammation. Mechanistically, we show that NKILA is able to positively mediate the expression of KLF4, an anti-inflammatory atheroprotective regulator in endothelial cells (ECs), by a NF-κB-mediated DNA methylation mechanism. Moreover, NF-κB is found to help recruit DNMT3A to the CpG island of KLF4 promoter, facilitating KLF4 promoter DNA methylation and transcriptional repression. More importantly, we find KLF4 can inversely attenuate NF-κB transcriptional activity via establishing a NF-κB/KLF4 positive feedback loop, which is under the control of NKILA. Hence, sustained endothelium inflammation will occur, once the NKILA becomes dysfunctional. These studies revealed that NKILA can function as a vital regulator to protect the endothelium from inflammatory lesions and related vascular diseases.

A long noncoding RNA NR_045363 controls cardiomyocyte proliferation and cardiac repair.

Long noncoding RNAs (lncRNAs) play important roles in the regulation of genes involved in cell proliferation. We have previously sought to more globally understand the differences of lncRNA expression between human fetal heart and adult heart to identify some functional lncRNAs which involve in the process of heart repair. We found that a highly conserved long noncoding RNA NR_045363 was mainly expressed in cardiomyocytes and rarely in non-cardiomyocytes. NR_045363 overexpression in 7-day-old mice heart could improve cardiac function and stimulate cardiomyocyte proliferation after myocardial infarction. Furthermore, NR_045363 knockdown inhibited proliferation of primary embryonic cardiomyocytes, while NR_045363 overexpression enhanced DNA synthesis and cytokinesis in neonatal cardiomyocytes in vitro. Mechanistic analysis revealed that NR_045363 promoted cardiomyocyte proliferation through interaction with miR-216a, which regulated the JAK2-STAT3 pathway. Our results showed that NR_045363 is a potent lncRNA modulator essential for cardiomyocyte proliferation.

Induced pluripotent stem cell-conditional medium inhibits H9C2 cardiomyocytes apoptosis via autophagy flux and Wnt/ß-catenin pathway.

Induced pluripotent stem cell-derived conditioned medium (iPS-CM) could improve cell viability in many types of cells and may be a better alternative for the treatment of myocardial infarction. This study aimed to examine the influence of iPS-CM on anti-apoptosis and the proliferation of H9C2 cardiomyocytes and investigate the underlying mechanisms. H9C2 cardiomyocytes were exposed to 200 µmol/L hydrogen peroxide (H2 O2 ) for 24 hours with or without pre-treatment with iPS-CM. The ratio of apoptotic cells, the loss of mitochondrial membrane potential (△Ψm) and the levels of intracellular reactive oxygen species were analysed by flow cytometric analysis. The expression levels of BCL-2 and BAX proteins were analysed by Western blot. Cell proliferation was assessed using cell cycle and EdU staining assays. To study cell senescence, senescence-associated ß-galactosidase (SA-ß-gal) staining was conducted. The levels of malondialdehyde, superoxide dismutase and glutathione were also quantified using commercially available enzymatic kits. The results showed that iPS-CM containing basic fibroblast growth factor significantly reduced H2 O2 -induced H9C2 cardiomyocyte apoptosis by activating the autophagy flux pathway, promoted cardiomyocyte proliferation by up-regulating the Wnt/ß-catenin pathway and inhibited oxidative stress and cell senescence. In conclusion, iPS-CM effectively enhanced the cell viability of H9C2 cardiomyocytes and could potentially be used to inhibit cardiomyocytes apoptosis to treat myocardial infarction in the future.

Sulodexide attenuates endoplasmic reticulum stress induced by myocardial ischaemia/reperfusion by activating the PI3K/Akt pathway.

Acute myocardial ischaemia/reperfusion (MI/R) injury causes severe arrhythmias with a high rate of lethality. Extensive research focus on endoplasmic reticulum (ER) stress and its dysfunction which leads to cardiac injury in MI/R Our study evaluated the effects of sulodexide (SDX) on MI/R by establishing MI/R mice models and in vitro oxidative stress models in H9C2 cells. We found that SDX decreases cardiac injury during ischaemia reperfusion and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase and reduced malondialdehyde in mice plasm, increased Bcl-2 expression, decreased BAX expression in a mouse model of MI/R. In vitro, SDX exerted a protective effect by the suppression of the ER stress which induced by tert-butyl hydroperoxide (TBHP) treatment. Both of the in vivo and in vitro effects were involved in the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. Inhibition of PI3K/Akt pathway by specific inhibitor, LY294002, partially reduced the protective effect of SDX. In short, our results suggested that the cardioprotective role of SDX was related to the suppression of ER stress in mice MI/R models and TBHP-induced H9C2 cell injury which was through the PI3K/Akt signalling pathway.

Vph2 is required for protection against a reductive stress in Candida albicans.

Vph2 is a putative V-ATPase assembly factor. Our previous study has characterized its roles in localization of V-ATPase subunit, cell wall composition, hyphal development and virulence. In this study, our results further demonstrated that Vph2 was localized around the nucleus and in patches close to the periphery of the cell, indicating that Vph2 was located to the endoplasmic reticulum (ER), which was consistent with that in Saccharomyces cerevisiae. Disruption of VPH2 led to hypersensitivity to reducing stresses induced by dithiothreitol (DTT) and ß-mercaptoethanol (ß-ME), and displayed increased GSH content and up-regulation of unfolded protein response (UPR)-related genes, such as PRB1 and PMT4. However, the induced UPR and growth defect on ß-ME plates of vph2Δ/Δ mutant could be partly alleviated by the GSH-specific scavenger 1-chloro-2, 4-dinitrobenzene (CDNB). These results indicated that loss of VPH2 led to an increase in GSH levels, which induced the UPR and caused the defective growth on reductive stress induced by ß-ME. In summary, Vph2 is necessary to maintain resistance against reductive stresses.

IMM-H007, a novel small molecule inhibitor for atherosclerosis, represses endothelium inflammation by regulating the activity of NF-κB and JNK/AP1 signaling.

Endothelium inflammation has become a major risk factor for pathological development of atherosclerosis. IMM-H007 (H007), a small molecule compound, is previously reported to reduce inflammatory atherosclerosis. However, the regulatory role of H007 in endothelium inflammation is still unclear. Here, we characterize H007 as a critical repressor in regulation of endothelium inflammation. We find that H007 significantly inhibits monocyte adhesion to endothelial cells and its transendothelial migration. Mechanistically, H007 markedly represses TNFα-induced IκBα degradation and NF-κB nuclear translocation, therefore leading to NF-κB-mediated inflammatory suppression. Moreover, another inflammatory signaling JNK/c-Jun, which is always co-activated with NF-κB in response to pro-inflammatory stimuli, is also found to be restrained by H007 through reducing its phosphorylation status. Thus, we conclude that H007 negatively regulates endothelium inflammation through inactivating NF-κB and JNK/AP1 signaling. More importantly, this study provides us a new insight into understanding the molecular basis by which H007 regulates inflammatory atherosclerosis.

Short- and medium-term follow-up of transcatheter closure of perimembranous ventricular septal defects.

BACKGROUND: Transcatheter closure of perimembranous ventricular septal defects is one of the greatest challenges in interventional cardiology. Short- and midium-term follow-up data for large samples are limited. This report presents our experience with transcatheter closure of perimembranous ventricular septal defects using an occluder. METHODS: Two hundred fifty-three patients included in the database of the Second Affiliated Hospital and Yuying Children's Hospital from January 2011- December 2015 with transcatheter closure of perimembranous ventricular septal defects and discharged from follow-up. All patients were invited for clinical and transthoracic echocardiography, electrocardiogram, and thoracic radiography check-up. RESULTS: Device implantation was successful in 252 of 253 patients (99.6%). The median age was 42 months (range 27-216 months). The median follow-up duration was 36 months (range 6-60 months). The mean defect diameter was 3.5 ± 1.4 mm and the mean size of the ventricular septal defect rim below the aortic valve was 3.7 ± 1.8 mm. The mean diameter of the devices used was 4 mm. Thirty-seven patients developed arrhythmia after the procedure and recovered within 24 months; four patients had hemolysis and four had moderate tricuspid valve regurgitation. No other serious adverse event occurred during the follow-up period. CONCLUSION: Transcatheter closure of perimembranous ventricular septal defects using an occluder is safe and effective in most patients.

Association between miRNA-196a2 rs11614913 T>C polymorphism and Kawasaki disease susceptibility in southern Chinese children.

BACKGROUND: miRNAs play important roles in a variety of diseases. Thus, the association between miRNA-196a2 rs11614913 T>C polymorphism and Kawasaki disease susceptibility is still unknown. METHODS: We included 532 children with Kawasaki disease and 623 healthy children from South China, and their DNA was extracted for genotyping by TaqMan methodology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association. RESULTS: No significant associations were observed between the miRNA-196a2 rs11614913 T>C polymorphisms and Kawasaki disease risk (TC vs TT: adjusted OR = 1.04, 95% CI = 0.79-1.37; CC vs TT: adjusted OR = 0.87, 95% CI = 0.63-1.21; dominant model: adjusted OR = 0.99, 95% CI = 0.76-1.27; and recessive model: adjusted OR = 0.85, 95% CI = 0.64-1.13). There was also no significant correlation found in stratified analyses. CONCLUSION: This study suggests that miRNA-196a2 rs11614913 T>C may not be associated with Kawasaki disease susceptibility in a southern Chinese population. Larger, multicenter studies are needed to confirm our conclusions.

Association between left ventricular ejection fraction and Kawasaki disease shock syndrome.

OBJECTIVE: This study was performed to explore the clinical features of Kawasaki disease shock syndrome and analyse the association between the left ventricular ejection fraction and Kawasaki disease shock syndrome. METHODS: We retrospectively reviewed the medical records of all consecutive inpatients with Kawasaki disease at Wenzhou Medical University Second Affiliated Hospital and Yuying Children's Hospital in Wenzhou, China from January 2009 to December 2016. We compared the clinical characteristics, laboratory data, and left ventricular ejection fraction between patients with and without Kawasaki disease shock syndrome and analysed the effect of the left ventricular ejection fraction on Kawasaki disease shock syndrome under different clinical conditions of Kawasaki disease. RESULTS: In total, 1147 patients were diagnosed with Kawasaki disease. Of these 1147 patients, 17 were diagnosed with Kawasaki disease shock syndrome; 68 patients admitted to the hospital at the same time, ±2 weeks, with Kawasaki disease but without Kawasaki disease shock syndrome served as the control group. Compared with the control group, the Kawasaki disease shock syndrome group had a significantly higher incidence of coronary artery lesions, cardiac troponin I concentration, N-terminal prohormone of brain natriuretic peptide concentration, neutrophil count and ratio, alanine aminotransferase concentration, aspartate aminotransferase concentration, and C-reactive protein concentration and a significantly lower platelet count, serum albumin concentration, and left ventricular ejection fraction. A low left ventricular ejection fraction was associated with Kawasaki disease shock syndrome under different conditions of Kawasaki disease. CONCLUSION: Among patients with Kawasaki disease, cardiac injury is more likely in those with Kawasaki disease shock syndrome than without, and a low left ventricular ejection fraction may be associated with the development of Kawasaki disease shock syndrome.