Unravelling the impact of RNA methylation genetic and epigenetic machinery in the treatment of cardiomyopathy.

Cardiomyopathy (CM) represents a heterogeneous group of diseases primarily affecting cardiac structure and function, with genetic and epigenetic dysregulation playing a pivotal role in its pathogenesis. Emerging evidence from the burgeoning field of epitranscriptomics has brought to light the significant impact of various RNA modifications, notably N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), 2'-O-methylation (Nm), and 6,2'-O-dimethyladenosine (m6Am), on cardiomyocyte function and the broader processes of cardiac and vascular remodelling. These modifications have been shown to influence key pathological mechanisms including mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, inflammation, immune response, and myocardial fibrosis. Importantly, aberrations in the RNA methylation machinery have been observed in human CM cases and animal models, highlighting the critical role of RNA methylating enzymes and their potential as therapeutic targets or biomarkers for CM. This review underscores the necessity for a deeper understanding of RNA methylation processes in the context of CM, to illuminate novel therapeutic avenues and diagnostic tools, thereby addressing a significant gap in the current management strategies for this complex disease.

Diffuse Large B-Cell Lymphoma With Cardiac Invasion Presented as Acute Myocardial Infarction and Left Ventricular Hypertrophy: A Case Report.

Primary cardiac lymphoma is an exceedingly rare malignant tumor, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histological subtype. This disease has non-specific clinical manifestations, making early diagnosis crucial. However, DLBCL diagnosis is commonly delayed, and its prognosis is typically poor. Herein, we report the case of a 51-year-old male patient with DLBCL who presented with recurrent chest tightness for 4 months as the primary clinical symptom. The patient was admitted to the hospital and diagnosed with acute myocardial infarction and left ventricular hypertrophy with heart failure. Echocardiography revealed a progression from left ventricular thickening to local pericardial thickening and adhesion in the inferior and lateral walls of the left ventricle. Finally, pathological analysis of myocardial biopsy confirmed the diagnosis of DLBCL. After treatment with the R-CHOP chemotherapy regimen, the patient's chest tightness improved, and he was discharged. After 2 months, the patient succumbed to death owing to sudden ventricular tachycardia, ventricular fibrillation, and decreased blood pressure despite rescue efforts. Transthoracic echocardiography is inevitable for the early diagnosis of DLBCL, as it can narrow the differential and guide further investigations and interventions, thereby improving the survival of these patients.

Targeting ERBB2 and PIK3R1 as a therapeutic strategy for dilated cardiomyopathy: A single-cell sequencing and mendelian randomization analysis.

Background: Dilated cardiomyopathy (DCM) is widely recognized as a significant contributor to heart failure. Nevertheless, the absence of pharmaceutical interventions capable of reversing disease progression and improving prognosis underscores the imperative for additional research in this area. Methods: First, we identified and evaluated three gene sets, namely "SC-DCM", "EP-DCM" and "Drug", using big data and multiple bioinformatics analysis methods. Accordingly, drug-treatable ("Hub") genes in DCM were identified. Following this, four microarray expression profile datasets were employed to authenticate the expression levels and discriminatory efficacy of "Hub" genes. Additionally, mendelian randomization analysis was conducted to ascertain the causal association between the "Hub genes" and heart failure. Finally, the "DGIdb" was applied to identify "Hub" genes-targeted drugs. The "ssGSEA" algorithm assessed the level of immune cell infiltration in DCM. Results: Enrichment analysis showed that the "SC-DCM" and "EP-DCM" gene sets were closely associated with DCM. PIK3R1 and ERBB2 were identified as drug-treatable genes in DCM. Additional analysis using MR supported a causal relationship between ERBB2 and heart failure, but not PIK3R1. Moreover, PIK3R1 was positively correlated with immune activation, while ERBB2 was negatively correlated. We found that everolimus was a pharmacological inhibitor for both PIK3R1 and ERBB2. However, no pharmacological agonist was found for ERBB2. Conclusion: PIK3R1 and ERBB2 are drug-treatable genes in DCM. ERBB2 has a causal effect on heart failure, and its normal expression may play a role in preventing the progression of DCM to heart failure. In addition, there is a cross-expression of PIK3R1 and ERBB2 genes in both DCM and tumors. The adaptive immune system and PIK3R1 may be involved in DCM disease progression, while ERBB2 exerts a protective effect against DCM.

Deciphering the role of SMARCA4 in cardiac disorders: Insights from single-cell studies on dilated cardiomyopathy and coronary heart disease.

BACKGROUND: Dilated cardiomyopathy (DCM) and coronary heart disease (CHD) stand as two of the foremost causes of mortality. However, the comprehensive comprehension of the regulatory mechanisms governing DCM and CHD remains limited, particularly from the vantage point of single-cell transcriptional analysis. METHOD: We used the GSE121893 dataset from the GEO database, analyzing single-cell expressions with tools like DropletUtils, Seurat, and Monocle. We also utilized the GSVA package for comparing gene roles in DCM and CHD, Finally, we conducted qRT-PCR and Western blot analyses to measure the expression levels of SMARCA4, Col1A1, Col3A1 and α-SMA, and the role of SMARCA4 on fibroblasts were explored by EdU and Transwell assay. RESULTS: Our analysis identified six cell types in heart tissue, with fibroblasts showing the most interaction with other cells. DEGs in fibroblasts were linked to muscle development and morphogenesis. Pseudotime analysis revealed the dynamics of fibroblast changes in both the normal and disease groups and many transcription factors (TFs) potentially involved in this process. Among these TFs, SMARCA4 which was translated into protein BRG1, showed the most significantly difference. In vivo experiments have demonstrated that SMARCA4 indeed promoted fibroblasts proliferation and migration. CONCLUSION: This study provides a clearer understanding of cell-type dynamics in heart diseases, emphasizing the role of fibroblasts and the significance of SMARCA4 in their function. Our results offer insights into the cellular mechanisms underlying DCM and CHD, potentially guiding future therapeutic strategies.

Common molecular mechanism and immune infiltration patterns of thoracic and abdominal aortic aneurysms.

Background: Aortic disease (aortic aneurysm (AA), dissection (AD)) is a serious threat to patient lives. Little is currently known about the molecular mechanisms and immune infiltration patterns underlying the development and progression of thoracic and abdominal aortic aneurysms (TAA and AAA), warranting further research. Methods: We downloaded AA (includes TAA and AAA) datasets from the GEO database. The potential biomarkers in TAA and AAA were identified using differential expression analysis and two machine-learning algorithms. The discrimination power of the potential biomarkers and their diagnostic accuracy was assessed in validation datasets using ROC curve analysis. Then, GSEA, KEGG, GO and DO analyses were conducted. Furthermore, two immuno-infiltration analysis algorithms were utilized to analyze the common immune infiltration patterns in TAA and AAA. Finally, a retrospective clinical study was performed on 78 patients with AD, and the serum from 6 patients was used for whole exome sequencing (WES). Results: The intersection of TAA and AAA datasets yielded 82 differentially expressed genes (DEGs). Subsequently, the biomarkers (CX3CR1 and HBB) were acquired by screening using two machine-learning algorithms and ROC curve analysis. The functional analysis of DEGs showed significant enrichment in inflammation and regulation of angiogenic pathways. Immune cell infiltration analysis revealed that adaptive and innate immune responses were closely linked to AA progression. However, neither CX3CR1 nor HBB was associated with B cell-mediated humoral immunity. CX3CR1 expression was correlated with macrophages and HBB with eosinophils. Finally, our retrospective clinical study revealed a hyperinflammatory environment in aortic disease. The WES study identified disease biomarkers and gene variants, some of which may be druggable. Conclusion: The genes CX3CR1 and HBB can be used as common biomarkers in TAA and AAA. Large numbers of innate and adaptive immune cells are infiltrated in AA and are closely linked to the development and progression of AA. Moreover, CX3CR1 and HBB are highly correlated with the infiltration of immune cells and may be potential targets of immunotherapeutic drugs. Gene mutation research is a promising direction for the treatment of aortic disease.

Glycyrrhizic acid ameliorates myocardial ischemia-reperfusion injury in rats through inhibiting endoplasmic reticulum stress.

The purpose of this study was to investigate the role of glycyrrhizic acid (GA) in regulating myocardial ischemia-reperfusion injury (MIRI) in rats as well as the underlying mechanism. H9c2 cells were subjected to hypoxia/re-oxygenation (H/R) to mimic the MIRI in vitro, while a rat model of ischemia-reperfusion (I/R) was constructed by occlusion of the left anterior descending coronary artery for 0.5 h followed by 2 h of reperfusion. While flow cytometry and TUNEL assay were performed to analyze apoptosis in cells and myocardial tissue, echocardiography, hematoxylin and eosin staining, and Masson's trichrome staining were conducted to evaluate cardiac function and pathological changes, respectively. The levels of serum CK, CK-MB, LDH, AST, TNF-α, and IL-6 as well as the contents of MDA and SOD in tissues were measured by ELISA, while Western blot analysis was performed to detect the expression of endoplasmic reticulum stress (ERS)-related proteins. GA treatment significantly reduced apoptosis in H9c2 cells, while it alleviated left ventricular dysfunction, fibrosis and myocardial apoptosis, down-regulated the levels of CK, CK-MB, LDH, AST, TNF-α, IL-6, and MDA, and up-regulated SOD levels in I/R rats. Moreover, GA treatment led to a decrease in the expression of CHOP, GRP78, and p-PERK in both H/R cells and I/R rats. This study demonstrates that cardioprotective role of GA in MIRI may involve the attenuation of ERS-induced apoptosis and inflammation, potentially providing an alternative strategy for intervention of MIRI.

Multiomics Analysis of Transcriptome, Epigenome, and Genome Uncovers Putative Mechanisms for Dilated Cardiomyopathy.

OBJECTIVE: Multiple genes have been identified to cause dilated cardiomyopathy (DCM). Nevertheless, there is still a lack of comprehensive elucidation of the molecular characteristics for DCM. Herein, we aimed to uncover putative molecular features for DCM by multiomics analysis. METHODS: Differentially expressed genes (DEGs) were obtained from different RNA sequencing (RNA-seq) datasets of left ventricle samples from healthy donors and DCM patients. Furthermore, protein-protein interaction (PPI) analysis was then presented. Differentially methylated genes (DMGs) were identified between DCM and control samples. Following integration of DEGs and DMGs, differentially expressed and methylated genes were acquired and their biological functions were analyzed by the clusterProfiler package. Whole exome sequencing of blood samples from 69 DCM patients was constructed in our cohort, which was analyzed the maftools package. The expression of key mutated genes was verified by three independent datasets. RESULTS: 1407 common DEGs were identified for DCM after integration of the two RNA-seq datasets. A PPI network was constructed, composed of 171 up- and 136 downregulated genes. Four hub genes were identified for DCM, including C3 (degree = 24), GNB3 (degree = 23), QSOX1 (degree = 21), and APOB (degree = 17). Moreover, 285 hyper- and 321 hypomethylated genes were screened for DCM. After integration, 20 differentially expressed and methylated genes were identified, which were associated with cell differentiation and protein digestion and absorption. Among single-nucleotide variant (SNV), C>T was the most frequent mutation classification for DCM. MUC4 was the most frequent mutation gene which occupied 71% across 69 samples, followed by PHLDA1, AHNAK2, and MAML3. These mutated genes were confirmed to be differentially expressed between DCM and control samples. CONCLUSION: Our findings comprehensively analyzed molecular characteristics from the transcriptome, epigenome, and genome perspectives for DCM, which could provide practical implications for DCM.

Multiomics Analysis of Genetics and Epigenetics Reveals Pathogenesis and Therapeutic Targets for Atrial Fibrillation.

OBJECTIVE: This study is aimed at understanding the molecular mechanisms and exploring potential therapeutic targets for atrial fibrillation (AF) by multiomics analysis. METHODS: Transcriptomics and methylation data of AF patients were retrieved from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) and differentially methylated sites between AF and normal samples were screened. Then, highly expressed and hypomethylated and lowly expressed and hypermethylated genes were identified for AF. Weighted gene coexpression network analysis (WGCNA) was presented to construct AF-related coexpression networks. 52 AF blood samples were used for whole exome sequence. The mutation was visualized by the maftools package in R. Key genes were validated in AF using independent datasets. RESULTS: DEGs were identified between AF and controls, which were enriched in neutrophil activation and regulation of actin cytoskeleton. RHOA, CCR2, CASP8, and SYNPO2L exhibited abnormal expression and methylation, which have been confirmed to be related to AF. PCDHA family genes had high methylation and low expression in AF. We constructed two AF-related coexpression modules. Single-nucleotide polymorphism (SNP) was the most common mutation type in AF, especially T > C. MUC4 was the most frequent mutation gene, followed by PHLDA1, AHNAK2, and MAML3. There was no statistical difference in expression of AHNAK2 and MAML3, for AF. PHLDA1 and MUC4 were confirmed to be abnormally expressed in AF. CONCLUSION: Our findings identified DEGs related to DNA methylation and mutation for AF, which may offer possible therapeutic targets and a new insight into the pathogenesis of AF from a multiomics perspective.

Association between α1-antitrypsin and acute coronary syndrome.

α1-antitrypsin (AAT) is a protein released as part of the anti-inflammatory response. It regulates the activity of serine proteinases and has a crucial role in the pathogenesis of acute coronary syndrome (ACS). The present study aimed to examine its role in patients with ACS. The plasma samples of 117 patients were collected at the Cardiology Department of the Affiliated Hospital of Youjiang Medical University (Baise, China). These included 46 cases of ACS (who met the diagnostic criteria for ACS and had ≥50% luminal stenosis of any coronary vessel), 35 cases of stable angina (SA; with ≥50% luminal stenosis of any coronary vessel but in a stable condition) and 36 normal healthy controls (subjects with no luminal stenosis in their coronary arteries). Plasma AAT protein concentrations were measured by ELISA and clinical data were collected. The plasma levels of AAT protein in patients with ACS were lower than those in controls and cases of SA (P<0.05), and the levels tended to decrease with the number of coronary artery lesions involved. There were no significant associations of the expression of plasma AAT protein and the number of diseased vessels in patients or the degree of stenosis. There was no correlation between the plasma protein levels of AAT and Gensini scores of patients with ACS. In conclusion, the plasma AAT protein levels in patients with ACS may contribute to the occurrence and development of coronary artery disease.