Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo

James, Victoria; Nizamudeen, Zubair Ahmed; Lea, Daniel; Dottorini, Tania; Holmes, Terri; Johnson, Benjamin B.; Arkill, Kenton P.; Denning, Chris; Smith, James G W

doi:10.1089/scd.2021.0202

Cited by 20 publications

(21 citation statements)

References 56 publications

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“…In agreement, it has been demonstrated that hypoxia and inflammation significantly alter the protein and mRNA content of endothelial cell‐derived EVs, while growth factor stimulation changes the mRNA composition of cardiomyocyte EVs (de Jong et al., 2012; Gennebäck et al., 2013). Moreover, the miRnome profile of vascular SMC‐derived EVs can be altered during replicative senescence, whereas EVs from human‐induced pluripotent stem cells (hiPSCs) of hypertrophic cardiomyopathy patients display a distinct small nucleolar RNA (snoRNA) composition (James et al., 2021; Nguyen et al., 2021). However, it is currently unclear whether these changes result from a differential recognition or loading of small RNAs by the previously identified RNA‐binding proteins.…”

Section: Introductionmentioning

confidence: 99%

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system

Martins‐Marques

Girão

2022

The Journal of Physiology

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Cardiovascular diseases (CVDs), which encompass a myriad of pathological conditions that affect the heart and/or the blood vessels, remain the major cause of morbidity and mortality worldwide. By transferring a wide variety of bioactive molecules, including proteins and microRNAs (miRNAs), extracellular vesicles (EVs) are recognized as key players in long‐range communication across the cardiovascular system. It has been demonstrated that these highly heterogeneous nanosized vesicles participate both in the maintenance of homeostasis of the heart and vessels, and contribute to the pathophysiology of CVDs, thus emerging as promising tools for diagnosis, prognosis and treatment of multiple CVDs. In this review, we highlight the beneficial roles of EV‐mediated communication in regulating vascular homeostasis, and inter‐organ crosstalk as a potential mechanism controlling systemic metabolic fitness. In addition, the impact of EV secretion in disease development is described, particularly focusing on cardiac remodelling following ischaemia, atherogenesis and atrial fibrillation progression. Finally, we discuss the potential of endogenous and bioengineered EVs as therapeutic tools for CVDs, as well as the suitability of assessing the molecular signature of circulating EVs as a non‐invasive predictive marker of CVD onset and progression. This rapidly expanding field of research has established the role of EVs as key conveyors of both cardioprotective and detrimental signals, which might be of relevance in uncovering novel therapeutic targets and biomarkers of CVDs. image

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Section: Introductionmentioning

confidence: 99%

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system

Martins‐Marques

Girão

2022

The Journal of Physiology

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“…29 Another exciting possibility is to express HA-NL-tetraspanin reporters in genetically modified or patient-derived hiPSC-CMs that model cardiomyopathies associated with changes in the secretion or function of CM-EVs. 93,94,95 In this case, HA-NL-tetraspanin reporters could reveal the impact of genetic mutations or specific cardiomyopathy phenotypes on EV generation mechanisms. Finally, EVs isolated from HA-NL-tetraspanin-expressing cardiomyocytes could be used to study CM-EV uptake by other cell types in vitro , or even injected into the infarcted mouse heart to study their cardiac retention and biodistribution following MI.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and TNF-alpha modulate extracellular vesicle release from human induced pluripotent stem cell-derived cardiomyocytes

Viola,

Bebelman,

Maas

et al. 2024

Preprint

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Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in the heart under homeostatic and pathological conditions, such as myocardial infarction (MI). However, the basic mechanisms driving cardiomyocyte-derived EV (CM-EV) production following stress are poorly understood. In this study, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express NanoLuc-tetraspanin reporters. These modified hiPSC-CMs allow for robust quantification of CM-EV secretion from small numbers of cells without the need for time-consuming EV isolation techniques. We subjected these cells to a panel of small molecules to study their effect on CM-EV biogenesis and secretion under basal and stress-associated conditions. We observed that EV biogenesis is context-dependent in hiPSC-CMs. Nutrient starvation decreases CM-EV secretion while hypoxia increases the production of CM-EVs in a nSmase2-dependent manner. Moreover, the inflammatory cytokine TNF-α increased CM-EV secretion through a process involving NLRP3 inflammasome activation and mTOR signaling. Here, we detailed for the first time the regulatory mechanisms of EV biogenesis in hiPSC-CMs upon MI-associated stressors.

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“…Recently, Lu et al pointed out that the lncRNA SNHG12 is effective in protecting against hypoxia/reoxygenation-induced injury in myocardial cells ( 22 ). Furthermore, SNHG12 is a kind of snoRNAs, and these snoRNAs were predicted to have roles in post-translational modifications and alternative splicing, processes differentially regulated in HCM ( 23 ). Based on our study, downregulation of SNHG12 and the consequent upregulation of hsa-miR-217, hsa-miR-140-5p, and hsa-miR-508-3p and downregulation of hsa-miR-1244 and hsa-miR-876-3p may play important roles in the pathology of HCM.…”

Section: Discussionmentioning

confidence: 99%

SNHG 12 and hsa-miR-140-5P may play an important role in the ceRNA network related to hypertrophic cardiomyopathy

Zhai¹,

Guo²,

Zhou³

et al. 2023

J Thorac Dis

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Background: Competing endogenous RNA (ceRNA) networks play important roles in the mechanism and development of a variety of diseases. This study aimed to construct a ceRNA network of hypertrophic cardiomyopathy (HCM). Methods:We searched the Gene Expression Omnibus (GEO) database and then analyzed the RNAs of 353 samples to explore differentially expressed lncRNAs (DELs), microRNAs (miRNAs; DEMs), and messenger RNAs (DEmRNAs) during the progression of HCM. Weighted gene co-expression network analysis (WGCNA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and transcription factor (TF) prediction of miRNAs were also performed, and the GO terms, KEGG pathway terms, protein-protein interaction (PPI) network, and Pearson correlation network of the DEGs were visualized with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and through Pearson analysis. In addition, a ceRNA network related to HCM was constructed on the basis of the DELs, DEMs, and DEs. Finally, the function of the ceRNA network was explored via GO and KEGG enrichment analyses.Results: Through our analysis, 93 DELs (77 upregulated and 16 downregulated), 163 DEMs (91 upregulated and 72 downregulated), and 432 DEGs (238 upregulated and 194 downregulated) were screened.The functional enrichment analysis results for miRNAs showed that the miRNAs were mainly related to the VEGFR signaling network and the INFr pathway and were mainly regulated by TFs such as SOX1, TEAD1, and POU2F1. Gene set enrichment analysis (GSEA), GO analysis, and KEGG enrichment analysis showed that the DEGs were enriched in the Hedgehog signaling pathway, IL-17 signaling pathway, and TNF signaling pathway. In addition, a ceRNA network including 8 lncRNAs (e.g., LINC00324, SNHG12, and ALMS1-IT1), 7 miRNAs (e.g., hsa-miR-217, hsa-miR-184, and hsa-miR-140-5p), and 52 mRNAs (e.g., IGFBP5, TMED5, and MAGT1) was constructed. The results revealed that SNHG12, hsa-miR-140-5p, hsa-miR-217, TFRC, HDAC4, TJP1, IGFBP5, and CREB5 may form an important network involved in the pathology of HCM. Conclusions:The novel ceRNA network that we have demonstrated will provide new research points about molecular mechanisms of HCM.

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Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo

Cited by 20 publications

References 56 publications

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system

Hypoxia and TNF-alpha modulate extracellular vesicle release from human induced pluripotent stem cell-derived cardiomyocytes

SNHG 12 and hsa-miR-140-5P may play an important role in the ceRNA network related to hypertrophic cardiomyopathy

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