Broadcasters, receivers, functional groups of metabolites, and the link to heart failure by revealing metabolomic network connectivity.

BACKGROUND AND OBJECTIVE: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline. METHODS: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites. RESULTS: We identified metabolites associated with higher and lower risk of HF incidence, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. These associations were not confounded by the other metabolites due to uncovering the connectivity among metabolites and adjusting each association for the confounding metabolites. Examples of our findings include the direct influence of asparagine on glycine, both of which were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids, which are not synthesized in the human body and are obtained directly from the diet. CONCLUSION: Metabolites may play a critical role in linking genetic background and lifestyle factors to HF incidence. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates studying complex conditions like HF.

A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in anthracycline-induced cardiotoxicity.

BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study. METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes. RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines. CONCLUSION: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.

Plasma metabolomics reveals the shared and distinct metabolic disturbances associated with cardiovascular events in coronary artery disease.

Risk prediction for subsequent cardiovascular events remains an unmet clinical issue in patients with coronary artery disease. We aimed to investigate prognostic metabolic biomarkers by considering both shared and distinct metabolic disturbance associated with the composite and individual cardiovascular events. Here, we conducted an untargeted metabolomics analysis for 333 incident cardiovascular events and 333 matched controls. The cardiovascular events were designated as cardiovascular death, myocardial infarction/stroke and heart failure. A total of 23 shared differential metabolites were associated with the composite of cardiovascular events. The majority were middle and long chain acylcarnitines. Distinct metabolic patterns for individual events were revealed, and glycerophospholipids alteration was specific to heart failure. Notably, the addition of metabolites to clinical markers significantly improved heart failure risk prediction. This study highlights the potential significance of plasma metabolites on tailed risk assessment of cardiovascular events, and strengthens the understanding of the heterogenic mechanisms across different events.

Integrated proteomic and metabolomic profiling reveals novel insights on the inflammation and immune response in HFpEF.

BACKGROUND: The precise mechanisms leading to the development of heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. In this study, an integrative approach utilizing untargeted proteomics and metabolomics was employed to delineate the altered proteomic and metabolomic profiles in patients with HFpEF compared to healthy controls. MATERIALS AND METHODS: Data were collected from a prospective cohort consisting of 30 HFpEF participants and 30 healthy controls, matched by gender and age. plasma samples were analyzed by multi-omics platforms. The quantification of plasma proteins and metabolites was performed using data-independent acquisition-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), respectively. Additionally, Proteomic and metabolomic results were analyzed separately and integrated using correlation and pathway analysis. This was followed by the execution of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies to elucidate the biological relevance of the observed results. RESULTS: A total of 46 significantly differentially expressed proteins (DEPs) and 102 differentially expressed metabolites (DEMs) were identified. Then, GO and KEGG pathway enrichment analyses were performed by DEPs and DEMs. Integrated analysis of proteomics and metabolomics has revealed Tuberculosis and African trypanosomiasis pathways that are significantly enriched and the DEPs and DEMs enriched within them, are associated with inflammation and immune response. CONCLUSIONS: Integrated proteomic and metabolomic analyses revealed distinct inflammatory and immune response pathways in HFpEF, highlighting novel therapeutic avenues.

Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis.

Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.

The role of miR-128 and MDFI in cardiac hypertrophy and heart failure: Mechanistic.

Heart failure (HF) prognosis depends on various regulatory factors; microRNA-128 (miR-128) is identified as a regulator of cardiac fibrosis, contributing to HF. MyoD family inhibitor (MDFI), which is reported to be related with Wnt/ß-catenin pathway, is supposed to be regulated by miR-128. This study investigates the interaction between miR-128 and MDFI in cardiomyocyte development and elucidates its role in heart injury. Gene expression profiling assessed miR-128's effect on MDFI expression in HF using qPCR and Western blot analysis. Luciferase assays studied the direct interaction between miR-128 and MDFI. MTT, transwell, and immunohistochemistry evaluated the effects of miR-128 and MDFI on myocardial cells in mice HF. Genescan and luciferase assays validated the interaction between miR-128 and MDFI sequences. miR-128 mimics significantly reduced MDFI expression at mRNA and protein levels with decrease rate of 55%. Overexpression of miR-128 promoted apoptosis with the increase rate 65% and attenuated cardiomyocyte proliferation, while MDFI upregulation significantly enhanced proliferation. Elevated miR-128 levels upregulated Wnt1 and ß-catenin expression, whereas increased MDFI levels inhibited these expressions. Histological analysis with haematoxylin and eosin staining revealed that miR-128 absorption reduced MDFI expression, hindering cell proliferation and cardiac repair, with echocardiography showing corresponding improvements in cardiac function. Our findings suggest miR-128 interacts with MDFI, playing a crucial role in HF management by modulating the Wnt1/ß-catenin pathway. Suppression of miR-128 could promote cardiomyocyte proliferation, highlighting the potential value of the miR-128/MDFI interplay in HF treatment.

Unlocking cardioprotection: iPSC exosomes deliver Nec-1 to target PARP1/AIFM1 axis, alleviating HF oxidative stress and mitochondrial dysfunction.

BACKGROUND: Heart failure (HF) is characterized by oxidative stress and mitochondrial dysfunction. This study investigates the therapeutic potential of Necrostatin-1 (Nec-1) delivered through exosomes derived from induced pluripotent stem cells (iPSCs) to address these pathologies in HF. METHODS: An HF rat model was established, and comprehensive assessments were performed using echocardiography, hemodynamics, and ventricular mass index measurements. iPSCs were used to isolate exosomes, loaded with Nec-1, and characterized for efficient delivery into cardiomyocytes. The interaction between Nec-1-loaded exosomes (Nec-1-Exos), poly (ADP-ribose) polymerase 1 (PARP1), and apoptosis-inducing factor mitochondria-associated 1 (AIFM1) was explored. Gain-of-function experiments assessed changes in cardiomyocyte parameters, and histological analyses were conducted on myocardial tissues. RESULTS: Cardiomyocytes successfully internalized Nec-1-loaded exosomes, leading to downregulation of PARP1, inhibition of AIFM1 nuclear translocation, increased ATP and superoxide dismutase levels, reduced reactive oxygen species and malonaldehyde levels, and restored mitochondrial membrane potential. Histological examinations confirmed the modulation of the PARP1/AIFM1 axis by Nec-1, mitigating HF. CONCLUSIONS: iPSC-derived exosomes carrying Nec-1 attenuate oxidative stress and mitochondrial dysfunction in HF by targeting the PARP1/AIFM1 axis. This study proposes a promising therapeutic strategy for HF management and highlights the potential of exosome-mediated drug delivery.

Screening of Secretory Proteins Linking Major Depressive Disorder with Heart Failure Based on Comprehensive Bioinformatics Analysis and Machine Learning.

BACKGROUND: Major depressive disorder (MDD) plays a crucial role in the occurrence of heart failure (HF). This investigation was undertaken to explore the possible mechanism of MDD's involvement in HF pathogenesis and identify candidate biomarkers for the diagnosis of MDD with HF. METHODS: GWAS data for MDD and HF were collected, and Mendelian randomization (MR) analysis was performed to investigate the causal relationship between MDD and HF. Differential expression analysis (DEA) and WGCNA were used to detect HF key genes and MDD-associated secretory proteins. Protein-protein interaction (PPI), functional enrichment, and cMAP analysis were used to reveal potential mechanisms and drugs for MDD-related HF. Then, four machine learning (ML) algorithms (including GLM, RF, SVM, and XGB) were used to screen candidate biomarkers, construct diagnostic nomograms, and predict MDD-related HF. Furthermore, the MCPcounter algorithm was used to explore immune cell infiltration in HF, and MR analysis was performed to explore the causal effect of immunophenotypes on HF. Finally, the validation of the association of MDD with reduced left ventricular ejection fraction (LVEF) and the performance assessment of diagnostic biomarkers was accomplished based on animal models mimicking MDD. RESULTS: The MR analysis showed that the MDD was linked to an increased risk of HF (OR = 1.129, p < 0.001). DEA combined with WGCNA and secretory protein gene set identified 315 HF key genes and 332 MDD-associated secretory proteins, respectively. Through PPI and MCODE analysis, 78 genes were pinpointed as MDD-related pathogenic genes for HF. The enrichment analysis revealed that these genes were predominantly enriched in immune and inflammatory regulation. Through four ML algorithms, two hub genes (ISLR/SFRP4) were identified as candidate HF biomarkers, and a nomogram was developed. ROC analysis showed that the AUC of the nomogram was higher than 0.90 in both the HF combined dataset and two external cohorts. In addition, an immune cell infiltration analysis revealed the immune dysregulation in HF, with ISLR/SFRP4 displaying notable associations with the infiltration of B cells, CD8 T cells, and fibroblasts. More importantly, animal experiments showed that the expression levels of ISLR (r = -0.653, p < 0.001) and SFRP4 (r = -0.476, p = 0.008) were significantly negatively correlated with LVEF. CONCLUSIONS: The MR analysis indicated that MDD is a risk factor for HF at the genetic level. Bioinformatics analysis and the ML results suggest that ISLR and SFRP4 have the potential to serve as diagnostic biomarkers for HF. Animal experiments showed a negative correlation between the serum levels of ISLR/SFRP4 and LVEF, emphasizing the need for additional clinical studies to elucidate their diagnostic value.

Celastrol exerts antiarrhythmic effects in chronic heart failure via NLRP3/Caspase-1/IL-1ß signaling pathway.

OBJECTIVES: Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI. METHODS: Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24 hours. Nigericin was used to activate the NLRP3 inflammasome. RESULTS: Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway. CONCLUSIONS: Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1ß pathway.

The Off-Target Cardioprotective Mechanisms of Sodium-Glucose Cotransporter 2 Inhibitors: An Overview.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a novel class of glucose-lowering drugs, have revolutionized the management of heart failure with reduced and preserved ejection fraction, regardless of the presence of diabetes, and are currently incorporated in the heart failure guidelines. While these drugs have consistently demonstrated their ability to decrease heart failure hospitalizations in several landmark clinical trials, their cardioprotective effects are far from having been completely elucidated. In the past decade, a growing body of experimental research has sought to address the molecular and cellular mechanisms of SGLT2i in order to provide a better understanding of the off-target acute and chronic cardiac benefits, beyond the on-target renal effect responsible for blood glucose reduction. The present narrative review addresses the direct cardioprotective effects of SGLT2i, delving into the off-target mechanisms of the drugs currently approved for heart failure therapy, and provides insights into future perspectives.

Exploring Sirtuins: New Frontiers in Managing Heart Failure with Preserved Ejection Fraction.

With increasing research, the sirtuin (SIRT) protein family has become increasingly understood. Studies have demonstrated that SIRTs can aid in metabolism and affect various physiological processes, such as atherosclerosis, heart failure (HF), hypertension, type 2 diabetes, and other related disorders. Although the pathogenesis of HF with preserved ejection fraction (HFpEF) has not yet been clarified, SIRTs have a role in its development. Therefore, SIRTs may offer a fresh approach to the diagnosis, treatment, and prevention of HFpEF as a novel therapeutic intervention target.

Diagnostic and predictive abilities of myokines in patients with heart failure.

Myokines are defined as a heterogenic group of numerous cytokines, peptides and metabolic derivates, which are expressed, synthesized, produced, and released by skeletal myocytes and myocardial cells and exert either auto- and paracrine, or endocrine effects. Previous studies revealed that myokines play a pivotal role in mutual communications between skeletal muscles, myocardium and remote organs, such as brain, vasculature, bone, liver, pancreas, white adipose tissue, gut, and skin. Despite several myokines exert complete divorced biological effects mainly in regulation of skeletal muscle hypertrophy, residential cells differentiation, neovascularization/angiogenesis, vascular integrity, endothelial function, inflammation and apoptosis/necrosis, attenuating ischemia/hypoxia and tissue protection, tumor growth and malignance, for other occasions, their predominant effects affect energy homeostasis, glucose and lipid metabolism, adiposity, muscle training adaptation and food behavior. Last decade had been identified 250 more myokines, which have been investigating for many years further as either biomarkers or targets for heart failure management. However, only few myokines have been allocated to a promising tool for monitoring adverse cardiac remodeling, ischemia/hypoxia-related target-organ dysfunction, microvascular inflammation, sarcopenia/myopathy and prediction for poor clinical outcomes among patients with HF. This we concentrate on some most plausible myokines, such as myostatin, myonectin, brain-derived neurotrophic factor, muslin, fibroblast growth factor 21, irisin, leukemia inhibitory factor, developmental endothelial locus-1, interleukin-6, nerve growth factor and insulin-like growth factor-1, which are suggested to be useful biomarkers for HF development and progression.

Serum microRNA-125b-5p expression in patients with dilated cardiomyopathy combined with heart failure and its effect on myocardial fibrosis.

OBJECTIVE: This paper was performed to decipher the serum microRNA (miR)-125b-5p expression in patients with dilated cardiomyopathy (DCM) combined with heart failure (HF) and its effect on myocardial fibrosis. METHODS: Serum miR-125b-5p expression, LVEDD, LVESD, LVEF, LVFS, and NT-proBNP levels were evaluated in clinical samples. A rat DCM model was established by continuous intraperitoneal injection of adriamycin and treated with miR-125b-5p agomir and its negative control. Cardiac function, serum TNF-α, hs-CRP, and NT-proBNP levels, pathological changes in myocardial tissues, cardiomyocyte apoptosis, and the expression levels of miR-125b-5p and fibrosis-related factors were detected in rats. RESULTS: In comparison to the control group, the case group had higher levels of LVEDD, LVESD, and NT-pro-BNP, and lower levels of LVEF, LVFS, and miR-125b-5p expression levels. Overexpression of miR-125b-5p effectively led to the improvement of cardiomyocyte hypertrophy and collagen arrangement disorder in DCM rats, the reduction of blue-stained collagen fibers in the interstitial myocardium, the reduction of the levels of TNF-α, hs-CRP, and NT-proBNP and the expression levels of TGF-1ß, Collagen I, and α-SMA, and the reduction of the number of apoptosis in cardiomyocytes. CONCLUSION: Overexpression of miR-125b-5p is effective in ameliorating myocardial fibrosis.

[Shenfu Injection regulates macrophage polarization via TLR4/NF-κB pathway to reduce inflammation in chronic heart failure].

This study aimed to investigate the therapeutic effect of Shenfu Injection on mice with chronic heart failure(CHF) and its effect on macrophage polarization. C57BL/6J mice were randomly assigned to the normal and model groups. The CHF model was established by intraperitoneal injection of isoproterenol(ISO, 7.5 mg·kg~(-1), 28 d). The successful modeling was determined by asses-sing the cardiac function and N-terminal pro-brain natriuretic peptide(NT-proBNP). The modeled mice were randomly divided into the model group, Shenfu Injection group, and TAK-242 group, and were injected intraperitoneally with the corresponding drugs for 15 days. Cardiac function was evaluated using echocardiography. Hematoxylin-eosin(HE) staining was used to detect the pathomorphology. Enzyme-linked immunosorbent assay(ELISA) was used to detect the values of serum NT-proBNP, interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), IL-10, and arginase 1(Arg-1). Flow cytometry was applied to detect the relative content and M1/M2 polarization of cardiac macrophages. Quantitative polymerase chain reaction(qPCR) and Western blot were used to detect the changes in the Toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB) pathway-related mRNA and protein expressions. Compared with the normal group, mice in the model group had lower values of left ventricular ejection fraction(LVEF) and left ventricular fractional shorte-ning(LVFS), higher values of left ventricular internal diastolic end-diastolic(LVIDd), left ventricular internal diastolic end-systolic(LVIDs), NT-proBNP, TNF-α, and IL-6(P<0.01); the number of macrophages increased in cardiac tissues(P<0.05), and the values of M1-F4/80~+CD86~+ were increased(P<0.01), while the values of M2-F4/80~+CD163~+ decreased(P<0.05); the mRNA and protein expressions of TLR4, myeloid differentiation factor 88(MyD88), IκB kinase α(IKKα), and NF-κB p65 in myocardial tissues were significantly elevated(P<0.05, P<0.01). Compared with the model group, mice in the Shenfu Injection and TAK-242 groups showed elevated LVEF, LVFS, IL-10, and Arg-1 levels, and decreased LVIDd, LVIDs, NT-proBNP, TNF-α, and IL-6 levels(P<0.05, P<0.01); the cardiac F4/80~+CD11b~+(macrophage) and M1-F4/80~+ CD86~+ values were significantly down-regulated, while M2-F4/80~+CD163~+ values were increased(P<0.05, P<0.01); and the mRNA and protein expressions of TLR4, MyD88, IKKα, and NF-κB p65 in myocardial tissues were notably decreased(P<0.05, P<0.01). CHF mice have an imbalance of M1/M2 macrophage polarization, with M1-type macrophages predominating. Shenfu Injection promotes macrophage polarization towards M2, inhibits M1-type macrophage activation, and attenuates inflammatory responses in heart failure by regulating the TLR4/NF-κB signaling pathway.

[Effects of Luhong Yixin Granules on myocardial fibrosis in heart failure rats based on TGF-ß1/Smads signaling pathway].

To investigate the effects of Luhong Yixin Granules on myocardial fibrosis in rats with heart failure and its possible mechanism, a total of 60 male Wistar rats were randomly divided into the control group, model group, and low-, medium-and high-dose Luhong Yixin Granules groups, with 12 rats in each group. Except for those in the control group, rats in the other groups were induced by intraperitoneal injection of doxorubicin(DOX) into a rat model. After the Luhong Yixin Granules were dissolved in the same amount of normal saline, they were given by gavage at low, medium and high doses(2.8, 5.6, 11.2 g·kg~(-1)·d~(-1)), and the control group and the model group were given the same amount of normal saline by gavage for 40 days. After the end of dosing, echocardiography was used to measure left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS). Rat body weight(BW) and heart weight(HW) were calculated as HW/BW. Enzyme-linked immunosorbent assay was used to measure the levels of interleukin-6(IL-6), interleukin-17(IL-17), tumor necrosis factor-α(TNF-α), transforming growth factor-ß1(TGF-ß1), growth stimulation expressed gene 2 protein(ST2), N-terminal pro-B-type natriuretic peptide(NT-proBNP), galectin-3(Gal-3) and creatine kinase isoenzyme(CK-MB) in serum. Hematoxylin-eosin(HE) staining and Masson staining were used to observe the pathological morphology of myocardial tissue. Western blot and quantitative real-time polymerase chain reaction were used to detect the protein and mRNA expression levels of IL-6, IL-17, TNF-α, TGF-ß1, Smad3, Smad7, α-smooth muscle actin(α-SMA), and collagen Ⅰ(COL-Ⅰ), respectively. RESULTS:: showed that compared with those in the control group, LVEF, LVFS, and HW/BW in the model group were decreased(P<0.05), and the levels of IL-6, IL-17, TNF-α, TGF-ß1, ST2, NT-proBNP, Gal-3, and CK-MB were increased(P<0.05). HE staining showed inflammatory changes in myocardial tissue; Masson staining showed decreases in the cross-sectional area and ventricular cavity area of the heart, and myocardial fibrosis of varying degrees(P<0.05). The protein and mRNA expression of IL-6, IL-17, TNF-α, TGF-ß1, Smad3, α-SMA, and COL-Ⅰ were increased(P<0.05), and the protein and mRNA expression of Smad7 protein was decreased(P<0.01). Compared with those in the model group, LVEF, LVFS and HW/BW of the low-, medium-and high-dose Luhong Yixin Granules groups were increased(P<0.05), and the levels of IL-6, IL-17, TNF-α, TGF-ß1, ST2, NT-proBNP, Gal-3 and CK-MB were decreased(P<0.05). HE staining showed gradually reduced inflammatory changes of myocardial tissue, and Masson staining showed increased cross-sectional area and ventricular cavity area of the heart and decreased area of myocardial fibrosis(P<0.05). The protein and mRNA expression levels of IL-6, IL-17, TNF-α, TGF-ß1, Smad3, α-SMA, and COL-Ⅰ were decreased(P<0.05), while the protein and mRNA expression levels of Smad7 were increased(P<0.05). Luhong Yixin Granules may be of great value in the treatment of heart failure by regulating the TGF-ß1/Smads signaling pathway, inhibiting the expression of inflammation-related proteins, reducing the deposition of extracellular matrix, and alleviating myocardial fibrosis.

Transverse aortic constriction multi-omics analysis uncovers pathophysiological cardiac molecular mechanisms.

Time-course multi-omics data of a murine model of progressive heart failure (HF) induced by transverse aortic constriction (TAC) provide insights into the molecular mechanisms that are causatively involved in contractile failure and structural cardiac remodelling. We employ Illumina-based transcriptomics, Nanopore sequencing and mass spectrometry-based proteomics on samples from the left ventricle (LV) and right ventricle (RV, RNA only) of the heart at 1, 7, 21 and 56 days following TAC and Sham surgery. Here, we present Transverse Aortic COnstriction Multi-omics Analysis (TACOMA), as an interactive web application that integrates and visualizes transcriptomics and proteomics data collected in a TAC time-course experiment. TACOMA enables users to visualize the expression profile of known and novel genes and protein products thereof. Importantly, we capture alternative splicing events by assessing differential transcript and exon usage as well. Co-expression-based clustering algorithms and functional enrichment analysis revealed overrepresented annotations of biological processes and molecular functions at the protein and gene levels. To enhance data integration, TACOMA synchronizes transcriptomics and proteomics profiles, enabling cross-omics comparisons. With TACOMA (https://shiny.dieterichlab.org/app/tacoma), we offer a rich web-based resource to uncover molecular events and biological processes implicated in contractile failure and cardiac hypertrophy. For example, we highlight: (i) changes in metabolic genes and proteins in the time course of hypertrophic growth and contractile impairment; (ii) identification of RNA splicing changes in the expression of Tpm2 isoforms between RV and LV; and (iii) novel transcripts and genes likely contributing to the pathogenesis of HF. We plan to extend these data with additional environmental and genetic models of HF to decipher common and distinct molecular changes in heart diseases of different aetiologies. Database URL: https://shiny.dieterichlab.org/app/tacoma.

Effects of Different Exercise Intensities on the Rat Model of Heart Failure.

Heart failure (HF) is a clinical syndrome caused by the progression of various cardiac diseases to severe stages, and exercise training plays a positive role in the development of HF. This study aimed to investigate the impact of different intensities of exercise training on HF rats.In this study, we established two HF rat models by intraperitoneal injection of isoproterenol at 2.5 mg/kg/day and abdominal aortic coarctation. After exercise training for 4 weeks, the heart weight/body weight ratio and echocardiography results were measured. Moreover, the regulatory effect of different exercise intensities on myocardial function in HF model rats was verified using tissue staining, western blotting, and reagent kits.Exercise training had a bidirectional adjust effect on HF. A running training program of 20 minutes/time had the most significant effect on improving myocardial function in HF rats, whereas exercise intensity of 40 minutes/time or 50 minutes/time did not significantly improve myocardial function in HF rats. Moreover, exercise intensities of 20 minutes/time and 30 minutes/time could reduce the expression levels of the HF markers NT-proBNP and BNP in rats, but the effect was more significant at a duration of 20 minutes/time. We also found that compared with other exercise intensities, 20 minutes/time exercise intensity could significantly improve myocardial fibrosis, promote cardiomyocyte autophagy, and reduce apoptosis in combating HF.Furthermore, an exercise intensity of 20 minutes/time can significantly ameliorate the progression of HF. However, the degree of significance of increasing exercise intensity in improving HF progression is weakened or has no significant effect.