Progression Of Cardiomyopathy Research Articles

High-throughput proteomic analysis unveils metabolic and mitochondrial signaling rewiring by chronic ivabradine treatment in duchenne muscular dystrophy

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Austrian Science Fund (FWF) Objective Ivabradine (IVA) is indicated in symptomatic treatment of chronic stable angina, heart failure, and also in those who are unable to tolerate or have contraindications to the use of beta-blockers. It has been showed IVA may have cardiovascular benefits in Duchenne muscular dystrophy (DMD) patients. This study was aimed to investigate the sustained impact of chronic ivabradine (IVA) administration on cardiac function and potential underlying mechanism using high throutput proteomic analysis. Methods DMDmdx male and Sprague–Dawley wt (Sprague–Dawley) male rats were randomly allocated to vehicle (n = 6) or IVA (n=6; 10 mg/kg/day via drinking water for four months). Transthoracic echocardiography and unbiased proteomic analysis were performed to assess cardiac function and left ventricular (LV) tissue, respectively. Protein-protein interactions were graphically represented, and cluster analysis with subsequent enrichment analyses was conducted. Results Chronic IVA treatment significantly enhanced the LV ejection fraction (p<0.05 compared to vehicle-treated DMDmdx rats). Proteomic data identified possible transcription factors (SPI1, IRF1, PPARA), consistent with previous studies. The reduction in copper metabolic changes associated with DMD can be attributed to the upregulation of Atox1 following IVA treatment. Mitochondrial dysfunction was effectively mitigated by IVA, as indicated by the different abundance of mitochondrial proteins. In addition, intercellular adhesion molecule 1 showed a reduction in the number of animals treated with ivabradine, indicating a further positive effect of the treatment. Conclusion In summary, this study demonstrated the beneficial effects of IVA in DMDmdx rat hearts. Cluster analysis of proteomic data revealed notable changes in cardiac metabolism, inflammation, and mitochondrial function. Ivabradine has emerged as a potential therapeutic approach to address these shifts, while proteomic pathway analysis may uncover new drugable targets to alleviate cardiomyopathy progression in DMD.Interaction of IvabradinProtein-protein interaction network

Integrative Single-Cell Analysis of Cardiomyopathy Identifies Differences in Cell Stemness and Transcriptional Regulatory Networks among Fibroblast Subpopulations.

Cardiomyopathy encompasses a broad spectrum of diseases affecting myocardial tissue, characterized clinically by abnormalities in cardiac structure, heart failure, and/or arrhythmias. Clinically heterogeneous, major types include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RM), ischemic cardiomyopathy (ICM), among which DCM is more prevalent, while ICM exhibits higher incidence and mortality rates. Myocardial injury during cardiomyopathy progression may lead to myocardial fibrosis. Failure to intervene early and inhibit the process of myocardial fibrosis may culminate in heart failure. Cardiac fibroblasts constitute crucial cellular components determining the extent and quality of myocardial fibrosis, with various subpopulations exerting diverse roles in cardiomyopathy progression. Despite this, understanding of the cellular plasticity and transcriptional regulatory networks of cardiac fibroblasts in cardiomyopathy remains limited. Therefore, in this study, we conducted comprehensive single-cell analysis of cardiac fibroblasts in cardiomyopathy to explore differences in cellular plasticity and transcriptional regulatory networks among fibroblast subpopulations, with the aim of providing as many useful references as possible for the diagnosis, prognosis, and treatment of cardiomyopathy. Cells with mitochondrial gene expression comprising >20% of total expressed genes were excluded. Differential expression genes (DEGs) and stemness genes within cardiac fibroblast subpopulations were subjected to Gene Ontology (GO) analysis of biological processes (BP) and AUCell analysis. Monocle software was employed to analyze the pseudo-temporal trajectory of cardiac fibroblasts in cardiomyopathy. Additionally, the Python package SCENIC was utilized to assess enrichment of transcription factors and activity of regulators within cardiac fibroblast subpopulations in cardiomyopathy. Following batch effect correction, 179,927 cells were clustered into 32 clusters, designated as T_NK cells, endothelial cells, myeloid cells, fibroblasts, pericytes, SMCs, CMs, proliferating cells, EndoCs, and EPCs. Among them, 8148 fibroblasts were further subdivided into 4 subpopulations, namely C0 THBS4+ Fibroblasts, C1 LINC01133+ Fibroblasts, C2 FGF7+ Fibroblasts, and C3 AGT + Fibroblasts. Results from GO_BP and AUCell analyses suggest that C3 AGT + Fibroblasts may be associated with immune response activation, protein transport, and myocardial contractile function, correlating with disease progression in cardiomyopathy. Transcription factor enrichment analysis indicates that FOS is the most significant TF in C3 AGT + Fibroblasts, also associated with the M1 module, possibly implicated in protein hydrolysis, intracellular DNA replication, and cell proliferation. Moreover, correlation analysis of transcriptional regulatory activity between fibroblast subpopulations reveals a more pronounced heterogeneity within C3 AGT + Fibroblasts in cardiomyopathy. C3 AGT + Fibroblasts exhibit increased sensitivity towards adverse outcomes in cardiomyopathy, such as myocardial fibrosis and impaired cardiac contractile function, compared to other cardiac fibroblast subpopulations. The differential cellular plasticity and transcriptional regulatory activity between C3 AGT + Fibroblasts and other subgroups offer new perspectives for targeting fibroblast subpopulation activity to treat cardiomyopathy. Additionally, stemness genes EPAS1 and MYC, along with the regulator FOS, may play roles in modulating the biological processes of cardiac fibroblasts in cardiomyopathy.

The role and therapeutic potential of macrophages in the pathogenesis of diabetic cardiomyopathy.

This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy (DCM). It begins by discussing the origins and diverse subtypes of macrophages, elucidating their spatial distribution and modes of intercellular communication, thereby emphasizing their significance in the pathogenesis of DCM. The review then delves into the intricate relationship between macrophages and the onset of DCM, particularly focusing on the epigenetic regulatory mechanisms employed by macrophages in the context of DCM condition. Additionally, the review discusses various therapeutic strategies aimed at targeting macrophages to manage DCM. It specifically highlights the potential of natural food components in alleviating diabetic microvascular complications and examines the modulatory effects of existing hypoglycemic drugs on macrophage activity. These findings, summarized in this review, not only provide fresh insights into the role of macrophages in diabetic microvascular complications but also offer valuable guidance for future therapeutic research and interventions in this field.

Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus.

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle-a well-balanced diet and physical activity. There is also a group of compounds-including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others-that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM.

Progression of Diabetic cardiomyopathy among Type 2 Diabetic Patients: A Review Article

Progression of Diabetic cardiomyopathy among Type 2 Diabetic Patients: A Review Article

CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction

BackgroundThe progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated.MethodsCardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis and functional experiments.ResultsOur findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10.ConclusionsThe current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

Single-cell insights: pioneering an integrated atlas of chromatin accessibility and transcriptomic landscapes in diabetic cardiomyopathy

BackgroundDiabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM’s unique cell states and molecular landscape for targeted therapeutic interventions.MethodsSingle-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings.ResultsThis study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation.ConclusionOur integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.

Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy

PurposeUremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury. MethodsUCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2′,7′-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1 s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC). ResultsUCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy. ConclusionThis study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.

From Blunt Cardiac Injury to Heart Transplant Following Motorcycle Collision.

Traumatic coronary artery occlusion and dissection is an exceedingly rare complication of blunt cardiac injury (BCI), though it has been previously noted in a number of case reports. However, it can also lead to heart transplant, which to our knowledge has not been previously described in the literature. We present a case of a healthy 24-year-old man without significant past medical history who was in a motorcycle accident, resulting in sternal fracture and BCI. He was ultimately found to have thrombotic occlusion and dissection of his left anterior descending artery (LAD), requiring mechanical thrombectomy and drug-eluting stent, as well as subsequent hospitalizations and operations due to various complications. It was suspected that he went into ventricular fibrillation and had a second motorcycle collision, resulting in cardiogenic shock. Ultimately, his progression of ischemic cardiomyopathy and mitral regurgitation led to the need for heart transplant. Blunt cardiac injury with myocardial contusion has such a broad range of pathologies. It is essential that patients with these injury patterns raise a high level of suspicion for BCI and are followed closely with appropriate diagnostic testing and rapid intervention for best possible outcomes.

Pulsatile Flow Increases METTL14-induced m6A modification and attenuates septic cardiomyopathy: an experimental study.

Septic cardiomyopathy is a sepsis-mediated cardiovascular complication with severe microcirculatory malperfusion. Emerging evidence has highlighted the protective effects of pulsatile flow in case of microcirculatory disturbance, yet the underlying mechanisms are still elusive. The objective of this study was to investigate the mechanisms of N6-methyladenosine (m6A) modification in the alleviation of septic cardiomyopathy associated with extracorporeal membrane oxygenation (ECMO)-generated pulsatile flow. Rat model with septic cardiomyopathy was established and was supported under ECMO either with pulsatile or non-pulsatile flow. Peripheral perfusion index (PPI) and cardiac function parameters were measured using ultrasonography. Dot blot assay was applied to examine the m6A level, while qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure the expressions of related genes. RNA immunoprecipitation assay was performed to validate the interaction between molecules. The ECMO-generated pulsatile flow significantly elevates microcirculatory PPI, improves myocardial function, protects the endothelium, and prolongs survival in rat models with septic cardiomyopathy. The pulsatile flow mediates the METTL14-mediated m6A modification to zonula occludens- (ZO-) 1 mRNA which stabilizes the ZO-1 mRNA depending on the presence of YTHDF2. The pulsatile flow suppresses the PI3K-Akt signaling pathway, of which the downstream molecule Foxo1, a negative transcription factor of METTL14, binds to the METTL14 promoter and inhibits the METTL14-induced m6A modification. The ECMO-generated pulsatile flow increases METTL14-induced m6A modification in ZO-1 and attenuates the progression of septic cardiomyopathy, suggesting that pulsatility might be a new therapeutic strategy in septic cardiomyopathy by alleviating microcirculatory disturbance.

Pharmacological Inhibition of Succinyl Coenzyme A:3-Ketoacid Coenzyme A Transferase Alleviates the Progression of Diabetic Cardiomyopathy.

Pharmacological Inhibition of Succinyl Coenzyme A:3-Ketoacid Coenzyme A Transferase Alleviates the Progression of Diabetic Cardiomyopathy.

Post-translational modifications in diabetic cardiomyopathy.

The increasing attention towards diabetic cardiomyopathy as a distinctive complication of diabetes mellitus has highlighted the need for standardized diagnostic criteria and targeted treatment approaches in clinical practice. Ongoing research is gradually unravelling the pathogenesis of diabetic cardiomyopathy, with a particular emphasis on investigating various post-translational modifications. These modifications dynamically regulate protein function in response to changes in the internal and external environment, and their disturbance of homeostasis holds significant relevance for the development of chronic ailments. This review provides a comprehensive overview of the common post-translational modifications involved in the initiation and progression of diabetic cardiomyopathy, including O-GlcNAcylation, phosphorylation, methylation, acetylation and ubiquitination. Additionally, the review discusses drug development strategies for targeting key post-translational modification targets, such as agonists, inhibitors and PROTAC (proteolysis targeting chimaera) technology that targets E3 ubiquitin ligases.

The role of protein kinase A signaling in cardiomyopathy

Cardiomyopathy, a diverse group of heart muscle diseases, poses a significant challenge to global cardiovascular health. However, the intricate molecular mechanisms underlying cardiomyopathy, especially the pivotal role of protein kinase A (PKA) signaling pathways in its pathogenesis, remains unclear. The review synthesizes current research findings and highlights the multifaceted interactions between PKA and key cellular components implicated in cardiomyopathy progression. Moreover, this paper unfolds with an exploration of the normal physiological functions of PKA in cardiac cells, emphasizing its role in regulating crucial processes such as excitation-contraction coupling and cellular energy homeostasis. The article navigates through the dysregulation of PKA signaling observed in various forms of cardiomyopathy, including hypertrophic, dilated, and restrictive subtypes. Insightful analyses into the impact of PKA-mediated phosphorylation events on cardiac contractility, ion channel function, and mitochondrial dynamics shed light on the intricate interplay between signaling cascades and disease manifestation. Future clinical trials targeting the PKA signaling pathway are required to seek more effective and precise therapeutic approaches of cardiomyopathy.

Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy.

Background: Dysfunction in myocardial energy metabolism plays a vital role in the pathological process of Dilated Cardiomyopathy (DCM). However, the precise mechanisms remain unclear. This study aims to investigate the key molecular mechanisms of energy metabolism and potential therapeutic agents in the progression of dilated cardiomyopathy with heart failure. Methods: Gene expression profiles and clinical data for patients with dilated cardiomyopathy complicated by heart failure, as well as healthy controls, were sourced from the Gene Expression Omnibus (GEO) database. Gene sets associated with energy metabolism were downloaded from the Molecular Signatures Database (MSigDB) for subsequent analysis. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis were employed to identify key modules and genes related to heart failure. Potential biological mechanisms were investigated through Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the construction of a competing endogenous RNA (ceRNA) network. Molecular docking simulations were then conducted to explore the binding affinity and conformation of potential therapeutic drugs with hub genes. Results: Analysis of the left ventricular tissue expression profiles revealed that, compared to healthy controls, patients with dilated cardiomyopathy exhibited 234 differentially expressed genes and 2 genes related to myocardial energy metabolism. Additionally, Benzoylaconine may serve as a potential therapeutic agent for the treatment of dilated cardiomyopathy. Conclusion: The study findings highlight the crucial role of myocardial energy metabolism in the progression of Dilated Cardiomyopathy. Notably, Benzoylaconine emerges as a potential candidate for treating Dilated Cardiomyopathy, potentially exerting its therapeutic effects by targeted modulation of myocardial energy metabolism through NRK and NT5.

Effects of gas signaling molecule SO2 in cardiac functions of hyperthyroid rats.

Sulfur dioxide (SO2), a novel endogenous gas signaling molecule, is involved in the regulation of cardiac function. Exerting a key role in progression of hyperthyroidism-induced cardiomyopathy (HTC), myocardial fibrosis is mainly caused by myocardial apoptosis, leading to poor treatment outcomes and prognoses. This study aimed to investigate the effect of SO2 on the hyperthyroidism-induced myocardial fibrosis and the underlying regulatory mechanisms. Elisa, Masson staining, Western-Blot, transmission electron microscope, and immunofluorescence were employed to evaluate the myocardial interstitial collagen deposition, endoplasmic reticulum stress (ERS), apoptosis, changes in endogenous SO2, and Hippo pathways from in vitro and in vivo experiments. The study results indicated that the hyperthyroidism-induced myocardial fibrosis was accompanied by decreased cardiac function, and down-regulated ERS, apoptosis, and endogenous SO2-producing enzyme aspartate aminotransferase (AAT)1/2 in cardiac myocytes. In contrast, exogenous SO2 donors improved cardiac function, reduced myocardial interstitial collagen deposition, up-regulated AAT1/2, antagonized ERS and apoptosis, and inhibited excessive activation of Hippo pathway in hyperthyroid rats. In conclusion, the results herein suggested that SO2 inhibited the overactivation of the Hippo pathway, antagonized ERS and apoptosis, and alleviated myocardial fibrosis in hyperthyroid rats. Therefore, this study was expected to identify intervention targets and new strategies for prevention and treatment of HTC.

Transcriptomic Analyses and Experimental Validation Identified Immune-Related lncRNA-mRNA Pair MIR210HG-BPIFC Regulating the Progression of Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a disease in which the myocardium of the heart becomes asymmetrically thickened, malformed, disordered, and loses its normal structure and function. Recent studies have demonstrated the significant involvement of inflammatory responses in HCM. However, the precise role of immune-related long non-coding RNAs (lncRNAs) in the pathogenesis of HCM remains unclear. In this study, we performed a comprehensive analysis of immune-related lncRNAs in HCM. First, transcriptomic RNA-Seq data from both HCM patients and healthy individuals (GSE180313) were reanalyzed thoroughly. Key HCM-related modules were identified using weighted gene co-expression network analysis (WGCNA). A screening for immune-related lncRNAs was conducted within the key modules using immune-related mRNA co-expression analysis. Based on lncRNA-mRNA pairs that exhibit shared regulatory microRNAs (miRNAs), we constructed a competing endogenous RNA (ceRNA) network, comprising 9 lncRNAs and 17 mRNAs that were significantly correlated. Among the 26 lncRNA-mRNA pairs, only the MIR210HG-BPIFC pair was verified by another HCM dataset (GSE130036) and the isoprenaline (ISO)-induced HCM cell model. Furthermore, knockdown of MIR210HG increased the regulatory miRNAs and decreased the mRNA expression of BPIFC correspondingly in AC16 cells. Additionally, the analysis of immune cell infiltration indicated that the MIR210HG-BPIFC pair was potentially involved in the infiltration of naïve CD4+ T cells and CD8+ T cells. Together, our findings indicate that the decreased expression of the lncRNA-mRNA pair MIR210HG-BPIFC was significantly correlated with the pathogenesis of the disease and may be involved in the immune cell infiltration in the mechanism of HCM.

USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

Neutrophils are indispensable for adverse cardiac remodeling in heart failure

Persistent immune activation contributes significantly to left ventricular (LV) dysfunction and adverse remodeling in heart failure (HF). In contrast to their well-known essential role in acute myocardial infarction (MI) as first responders that clear dead cells and facilitate subsequent reparative macrophage polarization, the role of neutrophils in the pathobiology of chronic ischemic HF is poorly defined. To determine the importance of neutrophils in the progression of ischemic cardiomyopathy, we measured their production, levels, and activation in a mouse model of chronic HF 8 weeks after permanent coronary artery ligation and large MI. In HF mice, neutrophils were more abundant both locally in failing myocardium (more in the border zone) and systemically in the blood, spleen, and bone marrow, together with increased BM granulopoiesis. There were heightened stimuli for neutrophil recruitment and trafficking in HF, with increased myocardial expression of the neutrophil chemoattract chemokines CXCL1 and CXCL5, and increased neutrophil chemotactic factors in the circulation. HF neutrophil NETotic activity was increased in vitro with coordinate increases in circulating neutrophil extracellular traps (NETs) in vivo. Neutrophil depletion with either antibody-based or genetic approaches abrogated the progression of LV remodeling and fibrosis at both intermediate and late stages of HF. Moreover, analogous to murine HF, the plasma milieu in human acute decompensated HF strongly promoted neutrophil trafficking. Collectively, these results support a key tissue-injurious role for neutrophils and their associated cytotoxic products in ischemic cardiomyopathy and suggest that neutrophils are potential targets for therapeutic immunomodulation in this disease.

Hematopoietic Prostaglandin D Synthase Is Increased in Mast Cells and Pericytes in Autopsy Myocardial Specimens from Patients with Duchenne Muscular Dystrophy.

The leading cause of death for patients with Duchenne muscular dystrophy (DMD), a progressive muscle disease, is heart failure. Prostaglandin (PG) D2, a physiologically active fatty acid, is synthesized from the precursor PGH2 by hematopoietic prostaglandin D synthase (HPGDS). Using a DMD animal model (mdx mice), we previously found that HPGDS expression is increased not only in injured muscle but also in the heart. Moreover, HPGDS inhibitors can slow the progression of muscle injury and cardiomyopathy. However, the location of HPGDS in the heart is still unknown. Thus, this study investigated HPGDS expression in autopsy myocardial samples from DMD patients. We confirmed the presence of fibrosis, a characteristic phenotype of DMD, in the autopsy myocardial sections. Additionally, HPGDS was expressed in mast cells, pericytes, and myeloid cells of the myocardial specimens but not in the myocardium. Compared with the non-DMD group, the DMD group showed increased HPGDS expression in mast cells and pericytes. Our findings confirm the possibility of using HPGDS inhibitor therapy to suppress PGD2 production to treat skeletal muscle disorders and cardiomyopathy. It thus provides significant insights for developing therapeutic drugs for DMD.

Diabetic Cardiomyopathy and Cell Death: Focus on Metal-Mediated Cell Death.

Cardiac myocyte death is an essential initiator of the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), a disease that has been reported since 1972. Cardiac cell death has been detected in the hearts of patients with diabetes and in animal models, and the role of cell death in the pathogenesis of DCM has been extensively investigated. The first review by the authors, specifically focusing on "Cell death and diabetic cardiomyopathy," was published in the journal, Cardiovascular Toxicology in 2003. Over the past two decades, studies investigating the role of cardiac cell death in the pathogenesis of DCM have gained significant attention, resulting in the discovery of several new kinds of cell death involving different mechanisms, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. After the 20th anniversary of the review published in 2003, we now provide an update with a focus on the potential role of metal-mediated cell death, ferroptosis, and cuproptosis in the development of DCM in compliance with this special issue. The intent of our review is to further stimulate work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.