Leukocyte Ig-like receptor B4 (Lilrb4a) alleviates cardiac dysfunction and isoproterenol-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation.

BACKGROUND: Heart failure (HF) is usually accompanied by the activation of the sympathetic nerve, and the excessive activation of the sympathetic nerve also promotes cardiac remodeling and cardiac dysfunction. In the isoproterenol (ISO) induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation. Leukocyte immunoglobulin-like receptor B4a (Lilrb4a) is an immunosuppressive regulatory receptor and plays a vital role in cardiovascular disease. However, the effect of Lilrb4a on ventricular arrhythmias from ISO-induced mice model remains unclear. OBJECTIVE: The purpose of this study was to explore the role and molecular mechanism of Lilrb4a in ISO-induced arrhythmogenic remodeling. METHODS: Lilrb4a knockout mice and Lilrb4a overexpression mice were infused with ISO (15 mg/kg/24h, 4 weeks). Echocardiography and Histology were used to evaluate myocardial hypertrophy and cardiac structural remodeling. Surface ECG and Electrophysiological examination were used to evaluate cardiac electrical remodeling and the susceptibility to ventricular arrhythmias (VAs). qRT-PCR and Western Blotting were used to detect the expression levels of ion channel proteins and signal pathway proteins. RESULTS: The results discovered that ISO induced cardiac hypertrophy, fibrosis, and inflammation, and led to electrical remodeling and the occurrence of VAs. Lilrb4a alleviated cardiac structural and electrical remodeling and protected against the occurrence of VAs in ISO-induced mice by gain- or loss-of-function approaches. The mechanism is that Lilrb4a inhibited NF-kB signaling and p38 signaling activation medicated by TAK1. CONCLUSIONS: Lilrb4a alleviates cardiac dysfunction and isoproterenol-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation through the regulation of NF-kB signaling and p38 signaling activation.

Chart2Vec: A Universal Embedding of Context-Aware Visualizations.

The advances in AI-enabled techniques have accelerated the creation and automation of visualizations in the past decade. However, presenting visualizations in a descriptive and generative format remains a challenge. Moreover, current visualization embedding methods focus on standalone visualizations, neglecting the importance of contextual information for multi-view visualizations. To address this issue, we propose a new representation model, Chart2Vec, to learn a universal embedding of visualizations with context-aware information. Chart2Vec aims to support a wide range of downstream visualization tasks such as recommendation and storytelling. Our model considers both structural and semantic information of visualizations in declarative specifications. To enhance the context-aware capability, Chart2Vec employs multi-task learning on both supervised and unsupervised tasks concerning the cooccurrence of visualizations. We evaluate our method through an ablation study, a user study, and a quantitative comparison. The results verified the consistency of our embedding method with human cognition and showed its advantages over existing methods.

Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1.

Chronic pressure overload can cause pathological cardiac remodeling and eventually heart failure. The ubiquitin specific protease (USP) family proteins play a prominent role in regulating substrate protein degradation and cardiac structural and functional homeostasis. Although USP38 is expressed in the heart, uncertainty exists regarding the function of USP38 in pathological cardiac remodeling. We constructed and generated cardiac specific USP38 knockout mice and cardiac specific USP38 overexpression mice to assess the role of USP38 in pathological cardiac remodeling. Furthermore, we used co-immunoprecipitation (Co-IP) assays and western blot analysis to identify the molecular interaction events. Here, we reported that the expression of USP38 is significantly elevated under a hypertrophic condition in vivo and in vitro. USP38 deletion significantly mitigates cardiomyocyte enlargement in vitro and hypertrophic effect induced by pressure overload, while overexpression of USP38 markedly aggravates cardiac hypertrophy and remodeling. Mechanistically, USP38 interacts with TANK-binding kinase 1 (TBK1) and removes K48-linked polyubiquitination of TBK1, stabilizing p-TBK1 and promoting the activation of its downstream mediators. Overexpression of TBK1 in the heart of cardiac specific USP38 knockout mice partially counteracts the benefit of USP38 deletion on pathological cardiac remodeling. The TBK1 inhibitor Amlexanox significantly alleviates pressure overload induced-cardiac hypertrophy and myocardial fibrosis in mice with USP38 overexpression. Our results demonstrate that USP38 serves as a positive regulator of pathological cardiac remodeling and suggest that targeting the USP38-TBK1 axis is a promising treatment strategy for hypertrophic heart failure.

Anxiety disorder and cardiovascular disease: a two-sample Mendelian randomization study.

AIMS: Cardiovascular disease is the leading cause of death worldwide. Anxiety disorders are common psychiatric conditions associated with cardiovascular outcomes. This two-sample Mendelian randomization (MR) study investigated the causal relationship between anxiety disorders and coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS: Single nucleotide polymorphisms (SNPs) associated with anxiety disorders (16 730 cases; 101 021 controls) were obtained from the UK Biobank genome-wide association study (GWAS). Cardiovascular outcome data were derived from the FinnGen study (CHD: 21 012 cases and 197 780 controls; MI: 12 801 cases and 187 840 controls; HF: 23 397 cases and 194 811 controls; and AF: 22 068 cases and 116 926 controls). Inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode analyses examined causality. RESULTS: IVW analysis demonstrated significant causal relationships between anxiety disorders and increased risk of CHD [odds ratio (OR): 4.496; 95% confidence interval (CI): 1.777-11.378; P = 0.002], MI (OR: 5.042; 95% CI: 1.451-17.518; P = 0.011), and HF (OR: 3.255; 95% CI: 1.461-7.252; P = 0.004). No relationship was observed with AF (OR: 1.775; 95% CI: 0.612-5.146; P = 0.29). Other methods showed non-significant associations. Two-way analysis indicated no reverse causality. CONCLUSIONS: Anxiety disorders were causally associated with greater risk of CHD, MI, and HF but not AF among individuals of European descent. Further research on mediating mechanisms and in diverse populations is warranted.

miR-199a/b-3p inhibits HCC cell proliferation and invasion through a novel compensatory signaling pathway DJ-1\Ras\PI3K/AKT.

Several studies have reported the effects of DJ-1 gene and miR-199a/b-3p on HCC development. However, whether miR-199a/b-3p regulates HCC progression through a novel compensatory signaling pathway involving DJ-1, Ras, and PI3K/AKT remains unknown. We used (TCGA, HPA, miRWalk and Target scan) databases, cancer and para-tissue HCC patients, dual-luciferase reporter gene analysis, proteomic imprinting, qPCR, cell proliferation, scratch, transport, and flow cytometry to detect the molecular mechanism of DJ-1 and miR-199a/b-3p co-expression in HCC cell lines. Bioinformatics analysis showed that DJ-1 was highly expressed in HCC ((P < 0.001) were closely associated with tumor stage (T), portal vein vascular invasion, OS, DSS, and PFI (P < 0.05); miR-199a/b-3p was lowly expressed in HCC (P < 0.001), which was the upstream regulator of DJ-1. Spearman coefficient r = -0.113, P = 0.031; Dual luciferase gene report verified the negative targeting relationship between them P< 0.001; Western blotting demonstrated that miR-199a/b-3p could inhibit the protein expression of DJ-1, Ras and AKT(P < 0.05); The results of CCK8, cell scratch, Transwell migration and flow cytometry showed that OE + DJ-1 increased the proliferation, migration and invasion ability of HepG2 cells, and decreased the apoptosis process, and the differences were statistically significant (P < 0.05), while miR-199a/b-3p had the opposite effect (P < 0.05).

Low-intensity pulsed ultrasound treatment mitigates ventricular arrhythmias via inhibiting microglia-mediated neuroinflammation in heart failure rat model.

BACKGROUND: Sympathetic overactivation plays an important role in heart failure (HF)-induced ventricular arrhythmias (VAs). Microglia-mediated neuroinflammation could contribute to sympathetic overactivation. A previous study demonstrated that low-intensity pulsed ultrasound (LIPUS) could inhibit neuroinflammation. However, whether LIPUS could attenuate HF-induced VAs via inhibiting microglia-mediated neuroinflammation remains largely unknown. METHODS: Forth Sprague-Dawley male rats were averagely randomized into four groups: CTL (control) group, CTL + LIPUS group, HF group and HF + LIPUS. Surgical ligation of the coronary artery was used for induction of HF. In vivo electrophysiological study was performed to check VAs susceptibility. Left stellate ganglion (LSG) neural activity and heart rate variability (HRV) were used to test sympathetic nerve activity. RESULTS: Compared to the HF group, LIPUS treatment significantly ameliorated HF-induced cardiac hypertrophy, fibrosis, and dysfunction. In addition, LIPUS treatment markedly inhibited HF-induced VAs susceptibility and reversed gap junction remodeling. LIPUS treatment obviously inhibited microglial activation and neuroinflammation in PVN, sympathetic hyperactivity in the LSG and proinflammatory cytokines releases in the ventricle. P2X7/NLRP3 signaling pathway may be involved in the anti-arrhythmic effect of LIPUS treatment following HF. CONCLUSIONS: Our data demonstrated that LIPUS treatment protected against HF-induced VAs via alleviating microglia-mediated neuroinflammation, sympathetic overactivation and proinflammatory cytokines releases through inhibiting P2X7/NLRP3 signaling. This study provides novel insight into the therapeutic potential of LIPUS.

maresin2 fine-tunes ULK1 O-GlcNAcylation to improve post myocardial infarction remodeling.

BACKGROUND: Myocardial infarction (MI) is one of the common causes of hospitalization and death all over the world. Maresin2 (MaR2), a specialized pro-solving mediator of inflammation, has been consolidated to be a novel cytokine fine-tuning inflammatory cascade. However, the precise mechanism is still unknown. Here, we demonstrated that maresin2 relieved myocardial damage via ULK1 O-GlcNAc modification during MI. METHODS: The myocardial infarction model was established by ligating the left anterior descending artery (LAD). Echocardiography, histopathology, transmission electron microscope, and Western blot were used to evaluate cardiac function and remodeling. Furthermore, primary neonatal rat cardiomyocytes (NRCMs) were cultivated, and immunoprecipitation (IP) assays were performed to explore the specific mechanism. RESULTS: As suggested, maresin2 treatment protected cardiac function and ameliorated adverse cardiac remodeling. Furthermore, we found that maresin2 facilitated autophagy and inhibited apoptosis under the modulation of O-GlcNAcylation-dependent ULK1 activation. Meanwhile, we discovered that maresin2 treatment ameliorated the inflammation of myocardial cells by inhibiting the interaction of TAK1 and TAB1. CONCLUSIONS: Maresin2 is likely to promote autophagy while relieving apoptosis and inflammation of myocardial cells, thereby exerting a protective effect on the heart after MI.

Calliope-Net: Automatic Generation of Graph Data Facts via Annotated Node-Link Diagrams.

Graph or network data are widely studied in both data mining and visualization communities to review the relationship among different entities and groups. The data facts derived from graph visual analysis are important to help understand the social structures of complex data, especially for data journalism. However, it is challenging for data journalists to discover graph data facts and manually organize correlated facts around a meaningful topic due to the complexity of graph data and the difficulty to interpret graph narratives. Therefore, we present an automatic graph facts generation system, Calliope-Net, which consists of a fact discovery module, a fact organization module, and a visualization module. It creates annotated node-link diagrams with facts automatically discovered and organized from network data. A novel layout algorithm is designed to present meaningful and visually appealing annotated graphs. We evaluate the proposed system with two case studies and an in-lab user study. The results show that Calliope-Net can benefit users in discovering and understanding graph data facts with visually pleasing annotated visualizations.

Rapid diagnosis of rheumatoid arthritis and ankylosing spondylitis based on Fourier transform infrared spectroscopy and deep learning.

OBJECTIVE: Rheumatoid arthritis and Ankylosing spondylitis are two common autoimmune inflammatory rheumatic diseases that negatively affect activities of daily living and can lead to structural and functional disability, reduced quality of life. Here, this study utilized Fourier transform infrared (FTIR) spectroscopy on dried serum samples and achieved early diagnosis of rheumatoid arthritis and ankylosing spondylitis based on deep learning models. METHOD: A total of 243 dried serum samples were collected in this study, including 81 samples each from ankylosing spondylitis, rheumatoid arthritis, and healthy controls. Three multi-scale convolutional modules with different specifications were designed based on the multi-scale convolutional neural network (MSCNN) to effectively fuse the local features to enhance the generalization ability of the model. The FTIR was then combined with the MSCNN model to achieve a non-invasive, fast, and accurate diagnosis of ankylosing spondylitis, rheumatoid arthritis, and healthy controls. RESULTS: Spectral analysis shows that the curves and waveforms of the three spectral graphs are similar. The main differences are distributed in the spectral regions of 3300-3250 cm-1, 3000-2800 cm-1, 1750-1500 cm-1, and 1500-1300 cm-1, which represent: Amides, fatty acids, cholesterol, proteins with a carboxyl group, amide II, free amino acids, and polysaccharides. Four classification models, namely artificial neural network (ANN), convolutional neural network (CNN), improved AlexNet model, and multi-scale convolutional neural network (MSCNN) were established. Through comparison, it was found that the diagnostic AUC value of the MSCNN model was 0.99, and the accuracy rate was as high as 0.93, which was much higher than the other three models. CONCLUSION: The study demonstrated the superiority of MSCNN in distinguishing ankylosing spondylitis from rheumatoid arthritis and healthy controls. FTIR may become a rapid, sensitive, and non-invasive means of diagnosing rheumatism.

Dapansutrile Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in HFpEF Rats.

BACKGROUND: Numerous studies have demonstrated that NLRP3 inflammasomes are key players in the progression of atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF). This study aimed to analyse the effect of pharmacological inhibition of NLRP3 inflammasomes using dapansutrile (DAPA), an oral NLRP3-specific inhibitor. METHODS: Dahl salt-sensitive rats were fed a high-salt diet (HSD, 8% NaCl) to induce HFpEF. Either DAPA (200 mg/kg/day) or saline was administered daily via gavage for 4 weeks. Electrophysiological studies were performed to assess the AF inducibility. Confocal fluorescence microscopy and western blot analysis were used to study calcium handling. RESULTS: The DAPA-treated HFpEF rats were less prone to AF induction by programmed electrical stimulation. Atrial fibrosis and inflammation were attenuated in DAPA-treated HFpEF hearts. Dapansutrile treatment showed an increase in the Ca2+ transient sarcoplasmic reticulum-Ca2+ load, and protein expression of SERCA2; NCX1 and phosphorylation of PLB at Thr17 were decreased following DAPA treatment. The increased frequency of spontaneous Ca2+ spark in the HFpEF rats was related to the hyperphosphorylation of RyR2 at Ser2814, which was blunted in DAPA treatment. Dapansutrile treatment also decreased the phosphorylation of CaMKII expression in the HFpEF rats. Mechanistically, DAPA exerts an anti-arrhythmic effect, mainly by inhibiting activation of the NLRP3 inflammasome. CONCLUSION: These data provide evidence that the beneficial cardiac effects of DAPA are associated with reduced atrial inflammation and improved CaMKII-dependent Ca2+-handling abnormalities via blunting activation of the NLRP3 inflammasome, and DAPA may be beneficial in a rat model of HFpEF-induced AF.

Cardiac telerehabilitation under 5G internet of things monitoring: a randomized pilot study.

Owing to issues such as time and cost, patients often show poor acceptance of and adherence to center-based cardiac rehabilitation (CBCR), which impacts the effectiveness of rehabilitation. Therefore, there is growing interest in home-based cardiac rehabilitation and cardiac telerehabilitation (CTR), which entail less time and cost than CBCR. This study aimed to compare the changes in physiological and psychological indicators, compliance, and satisfaction after CTR and CBCR. In this single-blind, randomized, controlled trial, the intervention group received CTR via the 5G Internet of Things platform, while the control group received CBCR. Data from 50 patients (age 66.28 ± 4.01 years) with acute myocardial infarction who underwent percutaneous coronary intervention were analyzed. After an intervention period of three months, the maximal oxygen uptake and metabolic equivalent of task were 5.53 ± 0.12 and 19.32 ± 0.17, respectively, in the intervention group, and 4.15 ± 0.13 and 16.52 ± 0.18, respectively, in the control group. After three months of intervention, there were significant differences between the two groups in all observed indicators (p < 0.05), except for low-density lipoprotein and the incidence of major adverse cardiovascular events (p > 0.05). The use of a 5G Internet of Things platform cardiac rehabilitation model effectively improved outcomes in patients with acute myocardial infarction who underwent percutaneous coronary intervention. Trials registry: The study protocol was registered at Chinese Clinical Trials Registry (ChiCTR), first trial registration 07/08/2023, identification number ChiCTR2300074435.

Gallium-Doped Hydroxyapatite: Shape Transformation and Osteogenesis Activity.

In this study, we employed a chemical precipitation method to successfully synthesize nanoparticles of gallium-doped hydroxyapatite (Ga-HAp). The microstructure of Ga-HAp was precisely tailored by modulating the concentration of gallium ions. Our findings unequivocally demonstrate that gallium ions exert a pronounced inhibitory influence on the growth of HAp crystals, and this inhibitory potency exhibits a direct correlation with the concentration of gallium. Furthermore, gallium ions facilitate the metamorphosis of HAp nanoparticles, transitioning them from nanoneedles to nanosheets. It is worth noting, however, that gallium ions exhibit a limited capacity to substitute for calcium ions within the crystal lattice of HAp, with the maximum substitution rate capped at 4.85%. Additionally, gallium plays a pivotal role in constraining the release of ions from HAp, and this behavior remains consistent across samples with varying Ga doping concentrations. Our in vitro experiments confirm that Ga-doped HAp amplifies both the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells.

USP38 exacerbates atrial inflammation, fibrosis, and susceptibility to atrial fibrillation after myocardial infarction in mice.

BACKGROUND: Inflammation plays an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). The role of USP38, a member of the ubiquitin-specific protease family, on MI-induced atrial inflammation, fibrosis, and associated AF is unclear. METHODS: In this study, we surgically constructed a mouse MI model using USP38 cardiac conditional knockout (USP38-CKO) and cardiac-specific overexpression (USP38-TG) mice and applied biochemical, histological, electrophysiological characterization and molecular biology to investigate the effects of USP38 on atrial inflammation, fibrosis, and AF and its mechanisms. RESULTS: Our results revealed that USP38-CKO attenuates atrial inflammation, thereby ameliorating fibrosis, and abnormal electrophysiologic properties, and reducing susceptibility to AF on day 7 after MI. USP38-TG showed the opposite effect. Mechanistically, The TAK1/NF-κB signaling pathway in the atria was significantly activated after MI, and phosphorylated TAK1, P65, and IκBα protein expression was significantly upregulated. USP38-CKO inhibited the activation of the TAK1/NF-κB signaling pathway, whereas USP38-TG overactivated the TAK1/NF-κB signaling pathway after MI. USP38 is dependent on the TAK1/NF-κB signaling pathway and regulates atrial inflammation, fibrosis, and arrhythmias after MI to some extent. CONCLUSIONS: USP38 plays an important role in atrial inflammation, fibrosis, and AF susceptibility after MI, providing a promising target for the treatment of AF after MI.

Vericiguat alleviates ventricular remodeling and arrhythmias in mouse models of myocardial infarction via CaMKII signaling.

AIMS: Maladaptive ventricular remodeling is a major cause of ventricular arrhythmias following myocardial infarction (MI) and adversely impacts the quality of life of affected patients. Vericiguat is a new soluble guanylate cyclase (sGC) activator with cardioprotective properties. However, its effects on MI-induced ventricular remodeling and arrhythmias are not fully comprehended; hence, our research evaluated the effect of vericiguat on mice post-MI. MATERIALS AND METHODS: Mice were divided into four treatment groups: Sham, Sham+Veri, MI, and MI + Veri. For the MI groups and MI + Veri groups, the left anterior descending (LAD) coronary artery was occluded to induce MI. Conversely, the Sham group underwent mock surgery. Vericiguat was administered orally daily for 28 days to the Sham+Veri and MI + Veri groups. Additionally, H9c2 cells were cultured for further mechanistic studies. Assessment methods included echocardiography, pathological analysis, electrophysiological analysis, and Western blotting. KEY FINDINGS: Vericiguat reduced cardiac dysfunction and infarct size after MI. It also mitigated MI-induced left ventricular fibrosis and cardiomyocyte apoptosis. Vericiguat normalized the expression of ion channel proteins (Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv7.1, KCNH2, Cav1.2) and the gap junction protein connexin 43, reducing the susceptibility to ventricular arrhythmia. Vericiguat significantly inhibited MI-induced calcium/calmodulin-dependent protein kinase II (CaMKII) pathway activation in mice. SIGNIFICANCE: Vericiguat alleviated MI-induced left ventricular adverse remodeling and arrhythmias through modulation of the CamkII signaling pathway.

USP38 regulates inflammatory cardiac remodeling after myocardial infarction.

BACKGROUND: The inflammatory response and subsequent ventricular remodeling are key factors contributing to ventricular arrhythmias (VAs) after myocardial infarction (MI). Ubiquitin-specific protease 38 (USP38) is a member of the USP family, but the impact of USP38 in arrhythmia substrate generation after MI remains unclear. This study aimed to determine the role of USP38 in post-MI VAs and its underlying mechanisms. METHODS AND RESULTS: Surgical left descending coronary artery ligation was used to construct MI models. Morphological, biochemical, histological, and electrophysiological studies and molecular analyses were performed after MI on days 3 and 28. We found that the USP38 expression was remarkably increased after MI. Cardiac-conditional USP38 knockout (USP38-CKO) reduces the expression of the inflammatory marker CD68 as well as the inflammatory factors TNF-α and IL-1ß after MI, thereby alleviating advanced cardiac fibrosis, electrical remodeling, ion channel remodeling, and susceptibility to VAs. In contrast, cardiac-specific USP38 overexpression (USP38-TG) showed a significant opposite effect, exacerbating the early inflammatory response and cardiac remodeling after MI. Mechanistically, USP38 knockout inhibited activation of the TAK1/NF-κB signaling pathway after MI, whereas USP38 overexpression enhanced activation of the TAK1/NF-κB signaling pathway after MI. CONCLUSIONS: Our study confirms that USP38-CKO attenuates the inflammatory response, improves ventricular remodeling after myocardial infarction, and reduces susceptibility to malignant VA by inhibiting the activation of the TAK1/NF-κB pathway, with USP38-TG playing an opposing role. These results suggest that USP38 may be an important target for the treatment of cardiac remodeling and arrhythmias after MI.

5-Methoxytryptophan alleviates atrial structural remodeling in ibrutinib-associated atrial fibrillation.

Background: Ibrutinib is an effective and well-tolerated treatment for B-cell lymphomas but is associated with an increased risk of atrial fibrillation (AF) by altering the structure of the atrium. 5-Methoxytryptophan (5-MTP) inhibits inflammatory and fibrotic processes. This study aimed to determine the effects and mechanisms of 5-MTP on the underlying mechanisms of AF caused by ibrutinib. Methods: The effect of 5-MTP on ibrutinib-related AF was investigated in male Sprague Dawley rats using echocardiographic, electrophysiological, immunofluorescent, Masson staining, and molecular analyses. Rusults: The ibrutinib+5-MTP group showed (1) a lower incidence and shorter duration of AF and accelerated atrial conduction; (2) a decreased left atrial mass and left atrial diameter; (3) decreased myocardial fibrosis in the left atrium; (4) lower atrial inflammation; (5) increased sarcoplasmic reticulum Ca2+-ATPase 2a protein expression, decreased phosphorylation of phospholamban at Thr17, and decreased sodium/calcium exchanger 1 protein expression and phosphorylation of ryanodine receptor 2 at S2814; and (6) decreased phosphorylation of CaMKII expression. 5-MTP treatment markedly activated the PI3K-Akt signaling. Inhibiting PI3K-Akt signaling significantly reversed the protective effect of 5-MTP on ibrutinib-related AF. Conclusions: These findings suggest that 5-MTP administration decreases the vulnerability of ibrutinib-related AF mainly caused by ameliorated maladaptive left atrial remodeling and dysregulation of calcium handling proteins. Mechanistically, 5-MTP treatment markedly enhanced the activation of cardiac PI3K-Akt signaling.

Columbianadin attenuates doxorubicin-induced cardiac injury, oxidative stress, and apoptosis via Sirt1/FOXO1 signaling pathway.

PURPOSE: Oxidative stress and apoptosis contribute to the pathological basis of doxorubicin (DOX)-induced cardiotoxicity. Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Herein, we intended to explore the potential role and molecular basis of CBN in DOX-induced cardiotoxicity. METHODS: C57BL/6 mice were subjected to DOX (15 mg/kg/day, i.p.) to generate DOX-induced cardiotoxicity. CBN (10 mg/kg/day, i.p.) was administered for four week following DOX injection. RESULTS: DOX administered markedly dampened cardiac function, increased cardiac injury, excessive reactive oxygen species (ROS) production, and cardiomyocyte loss. These alterations induced by DOX significantly alleviated by CBN treatment. Mechanistically, our results demonstrated that the CBN exerts cardioprotection role against DOX by up-regulating silent information regulator 1 (Sirt1) and decreasing acetylation of forkhead box O1 (FOXO1). Moreover, Sirt1 inhibition with Ex-527 significantly blunt the beneficial effect of CBN on DOX-induced cardiotoxicity, including cardiac dysfunction, ROS, and apoptosis. CONCLUSION: Collectively, CBN attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity through maintaining Sirt1/FOXO1 signaling pathway. Our results demonstrated that CBN might be used to treat DOX-related cardiotoxicity.

Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway.

BACKGROUNDS: Sepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, possess cardio-protective, their effects on sepsis-induced cardiomyopathy remain unknown. METHODS: C57BL/6 mice received subcutaneous injections of tirzepatide once a day for 14 days before subjected to LPS challenge for 12 h. LPS-induced cardiac dysfunction and its potential mechanisms were estimated by pathological analysis, echocardiographic measurement, electrocardiography, langendorff-perfused heart and molecular analysis. RESULTS: Pretreatment with tirzepatide attenuates LPS-induced cardiac dysfunction. tirzepatide remarkably reduces LPS-mediated inflammatory responses by inhibiting  the cardiac protein levels of TNF-α, IL-6, and IL-1B in mice. Interestingly, tirzepatide administration also improves cardiomyocytes apoptosis caused by LPS treatment. Furthermore, the protective roles of irzepatide against LPS-mediated increased inflammatory responses and decreased cardiomyocytes apoptosis are partially blunted by inhibiting TLR4/NF-kB/NLRP3 inflammation signaling. In addition, tirzepatide reduce the susceptibility ventricular arrhythmia in LPS-treated mice. CONCLUSION: In brief, tirzepatide attenuates LPS-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway.

Phenylacetylglutamine increases the susceptibility of ventricular arrhythmias in heart failure mice by exacerbated activation of the TLR4/AKT/mTOR signaling pathway.

BACKGROUND: Intestinal microbial metabolites are a risk factor for cardiovascular diseases, and phenylacetylglutamine (PAGln) is a newly discovered intestinal metabolite in the latest study. In addition, elevated plasma PAGln concentration was associated with increased mortality and hospitalization rates in patients with heart failure (HF). However, the mechanism of PAGln leading to increased HF mortality is unclear. The present study was performed to investigate whether the PAGln deteriorated the susceptibility of ventricular arrhythmias (VAs) in the setting of HF. METHODS: Thoracic aortic coarctation (TAC) was used to construct an animal model of HF in mice. Intraperitoneal injection of PAGln for 4 weeks intervened in HF mice. The concentration of PAGln was quantitatively determined by liquid chromatography-tandem mass spectrometry. Cardiac function was assessed by echocardiography; assessment of cardiac electrophysiological indexes was measured by electrocardiogram (ECG) and programmed electrical stimulation in isolated cardiac perfusion. Masson was stained for collagen deposition, and wheat germ agglutinin (WGA) was stained for the cross-sectional area of the myocytes. The qRT-PCR and Western Blotting were used to determine target gene expression in vivo and in vitro. RESULTS: PAGln promoted the activation of cardiac inflammation and fibrosis and deteriorated cardiac function in HF mice. Moreover, PAGln extended APD90, shortened the ERP/APD90 and increased the incidence of VAs following HF in isolated heart perfusion. Mechanistically, PAGln significantly enhanced the activation of the TLR4/AKT/mTOR signaling pathway in vivo and in vitro. CONCLUSIONS: PAGln increased the susceptibility of VAs in HF mice by activating the TLR4/AKT/mTOR signaling pathway.

Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in-depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD. METHODS AND RESULTS: Rats in the experimental group were intraperitoneally injected with a single dose of 60 mg/kg monocrotaline (MCT group, n = 32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n = 32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT + DAPA and CTL + DAPA groups) for a total of 4 weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4 weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P-wave duration (17.00 ± 0.53 ms, vs. 14.43 ± 0.57 ms in CTL; 14.00 ± 0.65 ms in CTL + DAPA; 14.57 ± 0.65 ms in MCT + DAPA; P < 0.05), RR interval (171.60 ± 1.48 ms, vs. 163.10 ± 1.10 ms in CTL; 163.30 ± 1.19 ms in CTL + DAPA; 163.10 ± 1.50 ms in MCT + DAPA; P < 0.05), Tpeak-Tend interval (65.93 ± 2.55 ms, vs. 49.55 ± 1.71 ms in CTL; 48.27 ± 3.08 ms in CTL + DAPA; P < 0.05), and corrected QT interval (200.90 ± 2.40 ms, vs. 160.00 ± 0.82 ms in CTL; 160.40 ± 1.36 ms in CTL + DAPA; 176.6 ± 1.57 ms in MCT + DAPA; P < 0.01) were significantly prolonged in the MCT group after 4 weeks, whereas P-wave amplitude (0.07 ± 0.0011 mV, vs. 0.14 ± 0.0009 mV in CTL; 0.14 ± 0.0011 mV in CTL + DAPA; 0.08 ± 0.0047 mV in MCT + DAPA; P < 0.05) and T-wave amplitude (0.04 ± 0.002 mV, vs. 0.13 ± 0.003 mV in CTL; 0.13 ± 0.003 mV in CTL + DAPA; P < 0.01) were decreased, and atrial 90% action potential duration (47.50 ± 0.93 ms, vs. 59.13 ± 2.1 ms in CTL; 59.75 ± 1.13 ms in CTL + DAPA; 60.63 ± 1.07 ms in MCT + DAPA; P < 0.01) and effective refractory periods (41.14 ± 0.88 ms, vs. 62.86 ± 0.99 ms in CTL; 63.14 ± 0.67 ms in CTL + DAPA; 54.86 ± 0.70 ms in MCT + DAPA; P < 0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL + DAPA; 40% in MCT + DAPA; P < 0.05) and duration of AF (30.85 ± 22.90 s, vs. 0 ± 0 s in CTL; 0.24 ± 0.76 s in CTL + DAPA; 5.08 ± 7.92 s in MCT + DAPA; P < 0.05) were significantly increased, whereas the expression levels of cardiac ion channels and calcium-handling proteins such as potassium/calcium channels and calmodulin were decreased. Mechanistically, 'NACHT, LRR, and PYD domain-containing protein 3' inflammasome-related pathway was significantly activated in the MCT group. Nevertheless, in the MCT + DAPA group, the above abnormalities were significantly improved. CONCLUSIONS: Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats.