Molecular Mechanisms of Cardiac Injury Associated With Myocardial SARS-CoV-2 Infection

  1. Xianfang Liu
  2. Longquan Lou
  3. Lei Zhou

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Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world. The development of cardiac injury is a common condition in patients with COVID-19, but the pathogenesis remains unclear. The RNA-Seq dataset (GSE150392) comparing expression profiling of mock human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and SARS-CoV-2-infected hiPSC-CMs was obtained from Gene Expression Omnibus (GEO). We identified 1,554 differentially expressed genes (DEGs) based on GSE150392. Gene set enrichment analysis (GSEA), Gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that immune-inflammatory responses were activated by SARS-CoV-2, while muscle contraction, cellular respiration, and cell cycle of hiPSC-CMs were inhibited. A total of 15 hub genes were identified according to protein–protein interaction (PPI), among which 11 upregulated genes were mainly involved in cytokine activation related to the excessive inflammatory response. Moreover, we identified potential drugs based on these hub genes. In conclusion, SARS-CoV-2 infection of cardiomyocytes caused a strong defensive response, leading to excessive immune inflammation, cell hypoxia, functional contractility reduction, and apoptosis, ultimately resulting in myocardial injury.

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  1. Version published to 10.3389/fcvm.2021.643958
  2. ScreenIT

    SciScore for 10.1101/2020.07.27.220954: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    , KEGG pathways functionally grouped networks and CLINVAR human diseases analysis using the CluGO (version 2.5.7) [12]and CluePedia (version 1.5.7) [13]apps of Cytoscape Software (Version3.8.0)[14]. 5. Protein-Protein Interaction (PPI) Network: The online tool of Search tool for the retrieval of interacting genes (STRING, https://string-db.org) [15]was applied to establish a PPIs of DEGs with score (median confidence) >0.4. Cytoscape and CytoHubba (Version 0.1) [16]was used to visualized the PPI network and identify hub genes.
    Version3.8.0
    suggested: None
    Software and Algorithms
    SentencesResources
    Data sources: We obtained the RNA-seq data (GSE150392) from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    package DESeq2 (version 1.28.1) to determine DEGs [9] (P adj < 0.01, | (log2FoldChange| > 2) between SARS-CoV-2 Infected hiPSC-CMs and Mock hiPSC-CMs.
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    Heatmap of DEGs was generated with R pheatmap package (version 1.0.12, https://CRAN.R-project.org/package=pheatmap). 3. Gene Set Enrichment Analysis (GSEA) of all detected genes: GSEA was performed using the GSEA software (version 4.0.3) implementation in our study for identifying potential hallmark of SARS-CoV-2 Infected hiPSC-CMs[10].
    pheatmap
    suggested: (pheatmap, RRID:SCR_016418)
    GSEA
    suggested: (SeqGSEA, RRID:SCR_005724)
    KEGG) pathway enrichment were analyzed using R package clusterProfiler (version 3.16.0)[11]
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    clusterProfiler
    suggested: (clusterProfiler, RRID:SCR_016884)
    , KEGG pathways functionally grouped networks and CLINVAR human diseases analysis using the CluGO (version 2.5.7) [12]and CluePedia (version 1.5.7) [13]apps of Cytoscape Software (Version3.8.0)[14]. 5. Protein-Protein Interaction (PPI) Network: The online tool of Search tool for the retrieval of interacting genes (STRING, https://string-db.org) [15]was applied to establish a PPIs of DEGs with score (median confidence) >0.4. Cytoscape and CytoHubba (Version 0.1) [16]was used to visualized the PPI network and identify hub genes.
    CLINVAR
    suggested: (ClinVar, RRID:SCR_006169)
    CluePedia
    suggested: (CluePedia Cytoscape plugin, RRID:SCR_015784)
    STRING
    suggested: (STRING, RRID:SCR_005223)
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)
    CytoHubba
    suggested: (cytoHubba, RRID:SCR_017677)
    GeneMANIA online database (https://genemania.org/) was used to analysis the hub genes[17].
    GeneMANIA
    suggested: (GeneMANIA, RRID:SCR_005709)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The current study has several limitations. The study included only one available data packet of 6 hiPSC-CMs samples in vitro, which could not fully reflect the effect of SRAS-COV-2 on the heart in vivo. Only bioinformatics analysis was conducted in this study, further clinical reports or in vitro studies are needed to support our conclusions.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. ScreenIT

    SciScore for 10.1101/2020.07.27.220954: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data sources: We obtained the RNA-seq data (GSE150392) from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO), RRID:SCR_005012)
    package DESeq2 (version 1.28.1) to determine DEGs [9] (P adj < 0.01, | (log2FoldChange| > 2) between SARS-CoV-2 Infected hiPSC-CMs and Mock hiPSC-CMs.
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    Heatmap of DEGs was generated with R pheatmap package (version 1.0.12, https://CRAN.R-project.org/package=pheatmap). 3. Gene Set Enrichment Analysis (GSEA) of all detected genes: GSEA was performed using the GSEA software (version 4.0.3) implementation in our study for identifying potential hallmark of SARS-CoV-2 Infected hiPSC-CMs[10].
    pheatmap
    suggested: (pheatmap, RRID:SCR_016418)
    GSEA
    suggested: (SeqGSEA, RRID:SCR_005724)
    KEGG) pathway enrichment were analyzed using R package clusterProfiler (version 3.16.0)[11]
    KEGG
    suggested: (KEGG, RRID:SCR_012773)
    clusterProfiler
    suggested: (clusterProfiler, RRID:SCR_016884)
    KEGG pathways functionally grouped networks and CLINVAR human diseases analysis using the CluGO (version 2.5.7) [12]and CluePedia (version 1.5.7) [13]apps of Cytoscape Software (Version3.8.0)[14]. 5. Protein-Protein Interaction (PPI) Network: The online tool of Search tool for the retrieval of interacting genes (STRING, https://string-db.org) [15]was applied to establish a PPIs of DEGs with score (median confidence) >0.4. Cytoscape and CytoHubba (Version 0.1) [16]was used to visualized the PPI network and identify hub genes.
    CLINVAR
    suggested: (ClinVar, RRID:SCR_006169)
    CluePedia
    suggested: (CluePedia Cytoscape plugin, RRID:SCR_015784)
    STRING
    suggested: (STRING, RRID:SCR_005223)
    CytoHubba
    suggested: (cytoHubba, RRID:SCR_017677)
    GeneMANIA online database (https://genemania.org/) was used to analysis the hub genes[17].
    GeneMANIA
    suggested: (GeneMANIA, RRID:SCR_005709)
    The data was imported into Cytoscape to calculate the topological characteristics of the network and determine each node.
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

    The current study has several limitations. The study included only one available data packet of 6 hiPSC-CMs samples in vitro, which could not fully reflect the effect of SRAS-COV-2 on the heart in vivo. Only bioinformatics analysis was conducted in this study, further clinical reports or in vitro studies are needed to support our conclusions.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  4. ScreenIT

    SciScore for 10.1101/2020.07.27.220954: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Methods: The RNA-Seq dataset (GES150392) compared expression profiling of mock human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and SARS-cov-2-infected hiPSC-CMs were obtained from Gene Expression Omnibus (GEO).
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO), SCR_005012)
    package DESeq2 (version 1.28.1) to determine DEGs [9] (P adj < 0.01, | (log2FoldChange| > 2) between SARS-CoV-2 Infected hiPSC-CMs and Mock hiPSC-CMs.
    DESeq2
    suggested: (DESeq, SCR_000154)
    Heatmap of DEGs was generated with R pheatmap package (version 1.0.12, https://CRAN.R-project.org/package=pheatmap). 3. Gene Set Enrichment Analysis (GSEA) of all detected genes: GSEA was performed using the GSEA software (version 4.0.3) implementation in our study for identifying potential hallmark of SARS-CoV-2 Infected hiPSC-CMs[10].
    pheatmap
    suggested: (pheatmap, SCR_016418)
          <div style="margin-bottom:8px">
        <div><b>GSEA</b></div>
        <div>suggested: (SeqGSEA, <a href="https://scicrunch.org/resources/Any/search?q=SCR_005724">SCR_005724</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">KEGG) pathway enrichment were analyzed using R package clusterProfiler (version 3.16.0)[11]</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>clusterProfiler</b></div>
        <div>suggested: (clusterProfiler, <a href="https://scicrunch.org/resources/Any/search?q=SCR_016884">SCR_016884</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">KEGG pathways functionally grouped networks and CLINVAR human diseases analysis using the CluGO (version 2.5.7) [12]and CluePedia (version 1.5.7) [13]apps of Cytoscape Software (Version3.8.0)[14]. 5. Protein-Protein Interaction (PPI) Network: The online tool of Search tool for the retrieval of interacting genes (STRING, https://string-db.org) [15]was applied to establish a PPIs of DEGs with score (median confidence) >0.4. Cytoscape and CytoHubba (Version 0.1) [16]was used to visualized the PPI network and identify hub genes.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>CluePedia</b></div>
        <div>suggested: (CluePedia Cytoscape plugin, <a href="https://scicrunch.org/resources/Any/search?q=SCR_015784">SCR_015784</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>STRING</b></div>
        <div>suggested: (STRING, <a href="https://scicrunch.org/resources/Any/search?q=SCR_005223">SCR_005223</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>Cytoscape</b></div>
        <div>suggested: (Cytoscape, <a href="https://scicrunch.org/resources/Any/search?q=SCR_003032">SCR_003032</a>)</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>CytoHubba</b></div>
        <div>suggested: (cytoHubba, <a href="https://scicrunch.org/resources/Any/search?q=SCR_017677">SCR_017677</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">GeneMANIA online database (https://genemania.org/) was used to analysis the hub genes[17].</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>GeneMANIA</b></div>
        <div>suggested: (GeneMANIA, <a href="https://scicrunch.org/resources/Any/search?q=SCR_005709">SCR_005709</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">The top 7 p-value KEGG pathways with its target genes were shown (Fig.4C). 5.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>KEGG</b></div>
        <div>suggested: (KEGG, <a href="https://scicrunch.org/resources/Any/search?q=SCR_012773">SCR_012773</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">COVID-19 caused by SARS-CoV-2 has been spreading in 216 countries/ areas/ territories, with over 12 ,000 ,000 confirmed cases (World Health Organization statistics as on July 13, 2020) [22].</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>SARS-CoV-2</b></div>
        <div>suggested: (Active Motif Cat# 91345, <a href="https://scicrunch.org/resources/Any/search?q=AB_2847847">AB_2847847</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Similar to clinically reported cardiac complications in COVID-19 patients, CLINVAR human diseases analysis shown SARS-CoV-2 infection may lead to myocardial infarction[39, 40], cardiomyopathy[41] and limb-girdle muscular dystrophy.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>CLINVAR</b></div>
        <div>suggested: (ClinVar, <a href="https://scicrunch.org/resources/Any/search?q=SCR_006169">SCR_006169</a>)</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Funding: This study was funded by National Natural Science Foundation of China (Grant/Award Numbers: “81970723”) Conflict of Interest: The authors declare that they have no conflict of interest.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>Numbers</b></div>
        <div>suggested: (BioNumbers, <a href="https://scicrunch.org/resources/Any/search?q=SCR_002782">SCR_002782</a>)</div>
      </div>
    </td></tr></table>

    Data from additional tools added to each annotation on a weekly basis.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2020.07.27.220954v1 on bioRxiv