Erratum to: Bioinformatic analysis for potential biological processes and key targets of heart failure-related stroke.

The original version of this article (Liu et al., 2021) unfortunately contained a mistake: statement of equal contribution is missing. This correction article shows that Chiyu LIU and Sixu CHEN contributed equally to this work. The original article has been corrected.

Allograft Model of Aortic Arch Segment Grafting to Abdominal Aorta Through End-to-Side Anastomosis in Mice.

The mouse aortic transplantation model is a valuable tool for investigating the mechanisms of atherosclerosis regression, but few laboratories can generate it due to the operation difficulty, especially for the style of end-to-side anastomosis, which facilitates syngeneic heterotopic transplanting a plaque-rich aortic arch into the abdominal aorta. Here we provide a modified protocol for generating this allograft model, which is capable of overcoming several critical surgical challenges such as separating a longer abdominal aorta segment, reducing bleeding and thrombosis, optimizing aortotomy, and improving end-to-side anastomosis to guarantee a potent graft. By transplanting plaque-rich aortic arches into the abdominal aorta of wildtype mice, a high operation success rate (over 90%) was noted with aortic clamping time under 60 min, the graft potency was satisfactory evidenced by examinations of micro-CT, ultrasound, and lower limb blood flow measurement, while a significant atherosclerosis regression was observed in the grafts at 1 week after transplantation.

LCZ696 (sacubitril/valsartan) inhibits pulmonary hypertension induced right ventricular remodeling by targeting pyruvate dehydrogenase kinase 4.

BACKGROUND: Right ventricular (RV) function is a major prognostic factor in patients with cardiopulmonary disease. Effective medical therapies are available for left heart failure, but they are usually less effective or even ineffective in right heart failure. Here, we tested the hypothesis that LCZ696 (sacubitril/valsartan) can attenuate pressure overload-induced RV remodeling by inhibiting pyruvate dehydrogenase kinase 4 (PDK4). METHODS: Adult male C57 mice were subjected to transverse aortic constriction (TAC), pulmonary artery constriction (PAC), or sham surgery. Bioinformatics analysis was used to screen for common differentially expressed genes (DEGs) between TAC and PAC. Chemical compounds targeting DEGs were predicted by molecular docking analysis. Effects of LCZ696 on PAC-induced RV remodeling and the associated PDK4-related mechanisms were investigated. RESULTS: We found 60 common DEGs between PAC and TAC, and Pdk4 was one of the downregulated DEGs. From 47 chemical compounds with potential cardiovascular activity and PDK4 protein binding ability, we selected LCZ696 to treat PAC-induced RV remodeling because of its high docking score for binding PDK4. Compared with vehicle-treated PAC mice, LCZ696-treated mice had significantly smaller RV wall thickness and RV diameters, less myocardial fibrosis, lower expression of PDK4 protein, and less phosphorylation of glycogen synthase kinase-3ß (p-GSK3ß). In PAC mice, overexpression of Pdk4 blocked the inhibitory effect of LCZ696 on RV remodeling, whereas conditional knockout of Pdk4 attenuated PAC-induced RV remodeling. CONCLUSIONS: Pdk4 is a common therapeutic target for pressure overload-induced left ventricular and RV remodeling, and LCZ696 attenuates RV remodeling by downregulating Pdk4 and inhibiting PDK4/p-GSK3ß signal.

Glycolysis Inhibition Alleviates Cardiac Fibrosis After Myocardial Infarction by Suppressing Cardiac Fibroblast Activation.

Objective: To explore the role of glycolysis in cardiac fibroblast (CF) activation and cardiac fibrosis after myocardial infarction (MI). Method: In vivo: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, was injected into the abdominal cavity of the MI or sham mice every day. On the 28th day, cardiac function was measured by ultrasonic cardiography, and the hearts were harvested. Masson staining and immunofluorescence (IF) were used to evaluate the fibrosis area, and western blot was used to identify the glycolytic level. In vitro, we isolated the CF from the sham, MI and MI with 2-DG treatment mice, and we also activated normal CF with transforming growth factor-ß1 (TGF-ß1) and block glycolysis with 2-DG. We then detected the glycolytic proteins, fibrotic proteins, and the concentrations of lactate and glucose in the culture medium. At last, we further detected the fibrotic and glycolytic markers in human fibrotic and non-fibrotic heart tissues with masson staining, IF and western blot. Result: More collagen and glycolytic protein expressions were observed in the MI mice hearts. The mortality increased when mice were treated with 2-DG (100 mg/kg/d) after the MI surgery (Log-rank test, P < 0.05). When the dosage of 2-DG declined to 50 mg/kg/d, and the treatment was started on the 4th day after MI, no statistical difference of mortality between the two groups was observed (Log-rank test, P = 0.98). The collagen volume fraction was smaller and the fluorescence signal of α-smooth muscle actin (α-SMA) was weaker in mice treated with 2-DG than PBS. In vitro, 2-DG could significantly inhibit the increased expression of both the glycolytic and fibrotic proteins in the activated CF. Conclusion: Cardiac fibrosis is along with the enhancement of CF activation and glycolysis. Glycolysis inhibition can alleviate cardiac fibroblast activation and cardiac fibrosis after myocardial infarction.

Bioinformatic analysis for potential biological processes and key targets of heart failure-related stroke.

This study aimed to uncover underlying mechanisms and promising intervention targets of heart failure (HF)-related stroke. HF-related dataset GSE42955 and stroke-related dataset GSE58294 were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was conducted to identify key modules and hub genes. Gene Ontology (GO) and pathway enrichment analyses were performed on genes in the key modules. Genes in HF- and stroke-related key modules were intersected to obtain common genes for HF-related stroke, which were further intersected with hub genes of stroke-related key modules to obtain key genes in HF-related stroke. Key genes were functionally annotated through GO in the Reactome and Cytoscape databases. Finally, key genes were validated in these two datasets and other datasets. HF- and stroke-related datasets each identified two key modules. Functional enrichment analysis indicated that protein ubiquitination, Wnt signaling, and exosomes were involved in both HF- and stroke-related key modules. Additionally, ten hub genes were identified in stroke-related key modules and 155 genes were identified as common genes in HF-related stroke. OTU deubiquitinase with linear linkage specificity(OTULIN) and nuclear factor interleukin 3-regulated(NFIL3) were determined to be the key genes in HF-related stroke. Through functional annotation, OTULIN was involved in protein ubiquitination and Wnt signaling, and NFIL3 was involved in DNA binding and transcription. Importantly, OTULIN and NFIL3 were also validated to be differentially expressed in all HF and stroke groups. Protein ubiquitination, Wnt signaling, and exosomes were involved in HF-related stroke. OTULIN and NFIL3 may play a key role in HF-related stroke through regulating these processes, and thus serve as promising intervention targets.

Identifying RBM47, HCK, CD53, TYROBP, and HAVCR2 as Hub Genes in Advanced Atherosclerotic Plaques by Network-Based Analysis and Validation.

Background: Atherosclerotic cardiovascular diseases accounted for a quarter of global deaths. Most of these fatal diseases like coronary atherosclerotic disease (CAD) and stroke occur in the advanced stage of atherosclerosis, during which candidate therapeutic targets have not been fully established. This study aims to identify hub genes and possible regulatory targets involved in treatment of advanced atherosclerotic plaques. Material/Methods: Microarray dataset GSE43292 and GSE28829, both containing advanced atherosclerotic plaques group and early lesions group, were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was conducted to identify advanced plaque-related modules. Module conservation analysis was applied to assess the similarity of advanced plaque-related modules between GSE43292 and GSE28829. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these modules were performed by Metascape. Differentially expressed genes (DEGs) were mapped into advanced plaque-related modules and module membership values of DEGs in each module were calculated to identify hub genes. Hub genes were further validated for expression in atherosclerotic samples, for distinguishing capacity of CAD and for potential functions in advanced atherosclerosis. Results: The lightgreen module (MElightgreen) in GSE43292 and the brown module (MEbrown) in GSE28829 were identified as advanced plaque-related modules. Conservation analysis of these two modules showed high similarity. GO and KEGG enrichment analysis revealed that genes in both MElightgreen and MEbrown were enriched in immune cell activation, secretory granules, cytokine activity, and immunoinflammatory signaling. RBM47, HCK, CD53, TYROBP, and HAVCR2 were identified as common hub genes, which were validated to be upregulated in advanced atherosclerotic plaques, to well distinguish CAD patients from non-CAD people and to regulate immune cell function-related mechanisms in advanced atherosclerosis. Conclusions: We have identified RBM47, HCK, CD53, TYROBP, and HAVCR2 as immune-responsive hub genes related to advanced plaques, which may provide potential intervention targets to treat advanced atherosclerotic plaques.

Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation.

Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related proteins were assessed in transforming growth factor beta 1 (TGF-ß1)-activated CF, whereas the role of mitochondrial fission during this process was also elucidated, as were the underlying mechanisms. The interaction between mitochondrial fission and mitophagy, the main defense mechanism against mitochondrial impairment, was also explored. The results showed that the mitochondria in TGF-ß1-treated CF were noticeably more fragmented than those of controls. The expression of several mitochondrial fission-related proteins was markedly upregulated, and the levels of fusion-related proteins were also altered, but to a lesser extent. Inhibiting mitochondrial fission resulted in a marked attenuation of TGF-ß1-induced CF activation. The TGF-ß1-induced increase in glycolysis was greatly suppressed in the presence of a mitochondrial inhibitor, whereas a glycolysis-specific antagonist exerted little additional antifibrotic effects. TGF-ß1 treatment increased cellular levels of reactive oxygen species (ROS) and triggered mitophagy, but this effect was reversed following the application of ROS scavengers. For the signals mediating mitophagy, the expression of Pink1, but not Bnip3l/Nix or Fundc1, exhibited the most significant changes, which could be counteracted by treatment with a mitochondrial fission inhibitor. Pink1 knockdown suppressed CF activation and mitochondrial fission, which was accompanied by increased CF apoptosis. In conclusion, mitochondrial fission resulted in increased glycolysis and played a crucial role in CF activation. Moreover, mitochondrial fission promoted reactive oxygen species (ROS) production, leading to mitophagy and the consequent degradation of the impaired mitochondria, thus promoting CF survival and maintaining their activation.

Influenza B virus-associated pneumonia in pediatric patients: clinical features, laboratory data, and chest X-ray findings.

BACKGROUND: The clinical significance of influenza B is frequently overlooked, and reports on influenza B pneumonia in children are limited. Therefore, the clinical features of associated complications have rarely been reported. The aim of this study is to evaluate the clinical characteristics in pediatric patients with influenza B virus-associated pneumonia. METHODS: From January 2009 to February 2012, 389 consecutive patients under 18 years old with influenza B virus infection were enrolled into the study. Thirty-four patients were defined as the pneumonia group by clinical symptoms and chest X-ray (CXR) findings, and 90 patients who had laboratory data and normal CXR findings were recruited to form the nonpneumonia group. RESULTS: The age of the patients in the pneumonia group was significantly younger (median of 5.3 vs. 6.6 years). The white blood cell count (median of 7.5 vs. 5.7 × 10(9) cells/L) and C-reactive protein level (median of 21.1 vs. 5.7 mg/L) were higher, but the hemoglobin level was lower (median of 12.6 vs. 13.2 g/dL) in the pneumonia group. The CXR findings revealed that 29.4% of patients had alveolar consolidation, 32.4% had interstitial infiltration, and 38.2% had ground glass opacity. Two of four patients with pleural effusion had a positive bacteria culture, and both of them died. CONCLUSION: Pneumonia should be considered in pediatric patients with influenza B virus infection presenting with younger age, higher white blood cell count, lower hemoglobin, and higher C-reactive protein level. The CXR findings were varied. Patients with pleural effusion and positive bacterial culture may have more severity of clinical outcome.

Controlling surface plasmon of several pair arrays of silver-shell nanocylinders.

We studied, numerically, the characteristics of the surface plasmon of a system consisting of several pair arrays of silver-shell nanocylinders. Effects from different numbers of pair arrays, illumination wavelengths, and the core refractive index of silver-shell nanocylinders are studied by using the finite-element method. Results show that the peak wavelengths shift to shorter wavelengths (blueshifted) when the number of pair arrays increases from three to six. The near-field intensities in the gaps of the proposed type 1 structure can be tuned much stronger with a redshift by varying the wavelength of the incident light. The main features of surface plasmon effects can be qualitatively understood from some simple models of three, four, five, and six pairs of silver-shell nanocylinders.