Whole-Transcriptome Profiling of Human Heart Tissues Reveals the Potential Novel Players and Regulatory Networks in Different Cardiomyopathy Subtypes of Heart Failure.
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ABSTRACT:
SUBMITTER: Liu CF
PROVIDER: S-EPMC7887094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe yak (Bos grunniens) is an important livestock species that can survive the extremely cold, harsh, and oxygen-poor conditions of the Qinghai-Tibetan Plateau and provide meat, milk, and transportation for the Tibetans living there. However, the regulatory network that drive this hypoxic adaptation remain elusive.ResultsThe heart tissues from LeiRoqi (LWQY) yak and their related cattle (Bos Taurus) breeds, which are two native cattle breeds located in high altitude (HAC) and low altitude (LAC) regions, respectively, were collected for RNA sequencing. A total of 178 co-differentially expressed protein-coding transcripts (co-DETs) were discovered in each of the LAC-vs-LWQY and LAC-vs-HAC comparison groups, including NFATC2, NFATC1, ENPP2, ACSL4, BAD, and many other genes whose functions were reported to be associated with the immune-system, endocrine-system, and lipid metabolism. Two and 230 lncRNA transcripts were differentially expressed in the LAC-vs-LWQY and LAC-vs-HAC comparisons' respectively, but no lncRNA transcripts that were co-differentially expressed. Among the 58 miRNAs that were co-differentially expressed, 18 were up-regulated and 40 were down-regulated. In addition, 640 (501 up-regulated and 139 down-regulated) and 152 (152 up-regulated and one down-regulated) circRNAs showed differential expression in LAC-vs-LWQY and LAC-vs-HAC comparison groups, respectively, and 53 up-regulated co-differentially expressed circRNAs were shared. Multiple co-DETs, which are the targets of miRNAs/lncRNAs, are significantly enriched in high-altitude adaptation related processes, such as, T cell receptor signaling, VEGF signaling, and cAMP signaling. A competing endogenous RNA (ceRNA) network was constructed by integrating the competing relationships among co-differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs. Furthermore, the hypoxic adaptation related ceRNA network was constructed, and the six mRNAs (MAPKAPK3, PXN, NFATC2, ATP7A, DIAPH1, and F2R), the eight miRNAs (including miR-195), and 15 circRNAs (including novel-circ-017096 and novel-circ-018073) are proposed as novel and promising candidates for regulation of hypoxic adaptation in the heart.ConclusionIn conclusion, the data recorded in the present study provides new insights into the molecular network of high-altitude adaptation along with more detailed information of protein-coding transcripts and non-coding transcripts involved in this physiological process, the detailed mechanisms behind how these transcripts "crosstalk" with each other during the plateau adaptation are worthy of future research efforts.
| S-EPMC8176224 | biostudies-literature
Project description:BackgroundCurrent heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures.ResultsRNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets.ConclusionsOur results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.
| S-EPMC6233272 | biostudies-literature
Project description:End stage heart failure due to ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) have similar characteristics, enlargement of the ventricles, relatively thin-walled ventricle, which leads to a limited contraction force and blood loading. Nevertheless, the response for present therapeutics is very variable and the prognosis is still very bad for ICM and DCM in general. Thus, the ability to differentiate the etiologies of heart failure based structural and physiological changes of the heart would be a step forward to enhance the specificity and the success of given therapy.
2007-10-31 | E-CVDE-1 | biostudies-arrayexpress
Project description:Colorectal cancer (CRC) remains a global disease burden and a leading cause of cancer related deaths worldwide. The identification of aberrantly expressed messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA), and the resulting molecular interactions and signaling networks is essential for better understanding of CRC, identification of novel diagnostic biomarkers and potential development of therapeutic interventions. Herein, we performed microRNA (miRNA) sequencing on fifteen CRC and their non-tumor adjacent tissues and whole transcriptome RNA-Seq on six paired samples from the same cohort and identified alterations in miRNA, mRNA, and lncRNA expression. Computational analyses using Ingenuity Pathway Analysis (IPA) identified multiple activated signaling networks in CRC, including ERBB2, RABL6, FOXM1, and NFKB networks, while functional annotation highlighted activation of cell proliferation and migration as the hallmark of CRC. IPA in combination with in silico prediction algorithms and experimentally validated databases gave insight into the complex associations and interactions between downregulated miRNAs and upregulated mRNAs in CRC and vice versa. Additionally, potential interaction between differentially expressed lncRNAs such as H19, SNHG5, and GATA2-AS1 with multiple miRNAs has been revealed. Taken together, our data provides thorough analysis of dysregulated protein-coding and non-coding RNAs in CRC highlighting numerous associations and regulatory networks thus providing better understanding of CRC.
| S-EPMC8280114 | biostudies-literature
Project description:Inflammation is a well-known feature of heart failure. Studies have shown that while some inflammation is required for repair during injury and is protective, prolonged inflammation leads to myocardial remodeling and apoptosis of cardiac myocytes. Various types of immune cells are implicated in myocardial inflammation and include neutrophils, macrophages, eosinophils, mast cells, natural killer cells, T cells, and B cells. Recent clinical trials have targeted inflammatory cascades as therapy for heart failure with limited success. A better understanding of the temporal course of the infiltration of the different immune cells and their contribution to the inflammatory process may improve the success for therapy. This brief review outlines the major cell types involved in heart failure, and some of their actions are summarized in the supplementary figure.
| S-EPMC6745095 | biostudies-literature
Project description:BACKGROUND:Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF). METHODS AND RESULTS:Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95% CI, 0.77-0.82 and external: 0.76; 95% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80-0.84) and validation samples (internal: 0.80; 95% CI, 0.78-0.83 and external: 0.76; 95% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison ?0.02). CONCLUSIONS:We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.
| S-EPMC4902276 | biostudies-literature
Project description:A large number of cannabinoids have been discovered that could play a role in mitigating cardiac affections. However, none of them has been as widely studied as cannabidiol (CBD), most likely because, individually, the others offer only partial effects or can activate potential harmful pathways. In this regard, CBD has proven to be of great value as a cardioprotective agent since it is a potent antioxidant and anti-inflammatory molecule. Thus, we conducted a review to condensate the currently available knowledge on CBD as a therapy for different experimental models of cardiomyopathies and heart failure to detect the molecular pathways involved in cardiac protection. CBD therapy can greatly limit the production of oxygen/nitrogen reactive species, thereby limiting cellular damage, protecting mitochondria, avoiding caspase activation, and regulating ionic homeostasis. Hence, it can affect myocardial contraction by restricting the activation of inflammatory pathways and cytokine secretion, lowering tissular infiltration by immune cells, and reducing the area of infarct and fibrosis formation. These effects are mediated by the activation or inhibition of different receptors and target molecules of the endocannabinoid system. In the final part of this review, we explore the current state of CBD in clinical trials as a treatment for cardiovascular diseases and provide evidence of its potential benefits in humans.
| S-EPMC7641267 | biostudies-literature
Project description:Chloroquine (CQ) and hydroxychloroquine (HCQ) are anti-rheumatic medications frequently used in the treatment of connective tissue disorders. We present the case of a 45-year-old woman with CQ-induced cardiomyopathy leading to severe heart failure. Electrocardiographic abnormalities included bifascicular block, while structural disease consisted of severe biventricular and biatrial hypertrophy. Appropriate diagnosis via endomyocardial biopsy led to cessation of CQ and subsequent dramatic improvement in symptoms and structural heart disease. Cardiac toxicity is an under-recognized adverse effect of CQ/HCQ leading to cardiomyopathy with concentric hypertrophy and conduction abnormalities, with the potential for significant morbidity and mortality. Predisposing factors for CQ/HCQ-induced cardiomyopathy have been proposed. CQ/HCQ cardiomyopathy is a phenocopy of Fabry disease, and α-galactosidase A polymorphism may account for some heterogeneity of disease presentation.
| S-EPMC5933951 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is the most common malignant brain tumor. GBM samples are classified into subtypes based on their transcriptomic and epigenetic profiles. Despite numerous studies to better characterize GBM biology, a comprehensive study to identify GBM subtype- specific master regulators, gene regulatory networks, and pathways is missing. Here, we used FastMEDUSA to compute master regulators and gene regulatory networks for each GBM subtype. We also ran Gene Set Enrichment Analysis and Ingenuity Pathway Analysis on GBM expression dataset from The Cancer Genome Atlas Project to compute GBM- and GBM subtype-specific pathways. Our analysis was able to recover some of the known master regulators and pathways in GBM as well as some putative novel regulators and pathways, which will aide in our understanding of the unique biology of GBM subtypes.
| S-EPMC4214595 | biostudies-literature
Project description:Aim - Pathological cardiac remodeling is characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here we aimed for a more detailed view on molecular changes driving cardiomyocyte hypertrophy and failure to aid in the development of therapies to reverse maladaptive remodeling. Methods and results - Utilizing cardiomyocyte-specific reporter mice exposed to pressure overload by transverse aortic banding (TAB), we obtained gene expression profiles of hypertrophic (one-week TAB) and failing (eight-weeks TAB) cardiomyocytes. We identified subsets of genes differentially regulated and specific for either stage. Among these, we found upregulation of known marker genes for HF, such as Nppb and Myh7. Additionally, we identified a set of genes specifically upregulated in failing cardiomyocytes and that so far have not been studied in HF, including the platelet isoform of phosphofructokinase (PFKP). Human cardiomyocytes subjected to 7-day NE/AngII treatment recapitulated the upregulation of the failure-induced genes indicating conservation. RNA-seq on failing and healthy human hearts confirmed increased expression for several failure-induced genes and allowed for expressional correlation to NPPB/MYH7. Finally, suppression of Pfkp in PE-treated primary cardiomyocytes reduced stress-induced gene expression and hypertrophy, suggesting a role in cardiomyocyte failure. Conclusion - Using cardiomyocyte-specific transcriptomic analysis we identified novel failure-induced genes relevant for human HF, and show that PFKP is a conserved failure-induced gene that can modulate cardiomyocyte stress response.
2020-09-15 | GSE138299 | GEO