The molecular mechanism of cardiac injury in SARS-CoV-2 infection: Focus on mitochondrial dysfunction

Shen, Yang; Chen, Min; Gu, Wei Yong; Wan, Jianwei; Cheng, Zhihui; Kan, Shuanglong; Zhang, Wen; He, Jianhua; Wang, Yunfeng; Deng, Xingqi

doi:10.1016/j.jiph.2023.03.015

Cited by 10 publications

(4 citation statements)

References 38 publications

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“…Various causes can lead to cardiomyocyte cytoskeleton protein dysfunction. ROS damage, ATP deficiency, and inflammation are likely to contribute to cardiomyocyte cytoskeleton protein dysfunction in the model of SARS-CoV-2 infection of hiPSC-CMs [ 28 ]. In the presence of increased ROS, energy disorders, inflammation, and cardiomyocyte cytoskeleton protein dysfunction, antioxidant genes such as CAT and SOD2 were significantly downregulated.…”

Section: Discussionmentioning

confidence: 99%

Decoding HiPSC-CM’s Response to SARS-CoV-2: mapping the molecular landscape of cardiac injury

Chen,

Fu,

Chen

et al. 2024

BMC Genomics

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Background Acute cardiac injury caused by coronavirus disease 2019 (COVID-19) increases mortality. Acute cardiac injury caused by COVID-19 requires understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly infects cardiomyocytes. This study provides a solid foundation for related studies by using a model of SARS-CoV-2 infection in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) at the transcriptome level, highlighting the relevance of this study to related studies. SARS-CoV-2 infection in hiPSC-CMs has previously been studied by bioinformatics without presenting the full molecular biological process. We present a unique bioinformatics view of the complete molecular biological process of SARS-CoV-2 infection in hiPSC-CMs. Methods To validate the RNA-seq datasets, we used GSE184715 and GSE150392 for the analytical studies, GSE193722 for validation at the cellular level, and GSE169241 for validation in heart tissue samples. GeneCards and MsigDB databases were used to find genes associated with the phenotype. In addition to differential expression analysis and principal component analysis (PCA), we also performed protein-protein interaction (PPI) analysis, functional enrichment analysis, hub gene analysis, upstream transcription factor prediction, and drug prediction. Results Differentially expressed genes (DEGs) were classified into four categories: cardiomyocyte cytoskeletal protein inhibition, proto-oncogene activation and inflammation, mitochondrial dysfunction, and intracellular cytoplasmic physiological function. Each of the hub genes showed good diagnostic prediction, which was well validated in other datasets. Inhibited biological functions included cardiomyocyte cytoskeletal proteins, adenosine triphosphate (ATP) synthesis and electron transport chain (ETC), glucose metabolism, amino acid metabolism, fatty acid metabolism, pyruvate metabolism, citric acid cycle, nucleic acid metabolism, replication, transcription, translation, ubiquitination, autophagy, and cellular transport. Proto-oncogenes, inflammation, nuclear factor-kappaB (NF-κB) pathways, and interferon signaling were activated, as well as inflammatory factors. Viral infection activates multiple pathways, including the interferon pathway, proto-oncogenes and mitochondrial oxidative stress, while inhibiting cardiomyocyte backbone proteins and energy metabolism. Infection limits intracellular synthesis and metabolism, as well as the raw materials for mitochondrial energy synthesis. Mitochondrial dysfunction and energy abnormalities are ultimately caused by proto-oncogene activation and SARS-CoV-2 infection. Activation of the interferon pathway, proto-oncogene up-regulation, and mitochondrial oxidative stress cause the inflammatory response and lead to diminished cardiomyocyte contraction. Replication, transcription, translation, ubiquitination, autophagy, and cellular transport are among the functions that decline physiologically. Conclusion SARS-CoV-2 infection in hiPSC-CMs is fundamentally mediated via mitochondrial dysfunction. Therapeutic interventions targeting mitochondrial dysfunction may alleviate the cardiovascular complications associated with SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Decoding HiPSC-CM’s Response to SARS-CoV-2: mapping the molecular landscape of cardiac injury

Chen,

Fu,

Chen

et al. 2024

BMC Genomics

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“…For instance, patients with COVID-19 exhibit notable mitochondrial dysfunction as well as metabolic disturbances marked by an upsurge in glycolysis in peripheral blood mononuclear cells (PBMCs) [ 59 ]. SARS-CoV-2 can also cause transcriptional downregulation of the mitochondrial respiratory chain complex and ATP synthesis in hiPSC-CMs [ 60 ]. Our and these previous studies demonstrate that mitochondrial dysfunction and metabolic alteration are involved in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Landscape of molecular crosstalk between SARS-CoV-2 infection and cardiovascular diseases: emphasis on mitochondrial dysfunction and immune-inflammation

Dai,

Cao,

Shen

et al. 2023

J Transl Med

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Background SARS-CoV-2, the pathogen of COVID-19, is a worldwide threat to human health and causes a long-term burden on the cardiovascular system. Individuals with pre-existing cardiovascular diseases are at higher risk for SARS-CoV-2 infection and tend to have a worse prognosis. However, the relevance and pathogenic mechanisms between COVID-19 and cardiovascular diseases are not yet completely comprehended. Methods Common differentially expressed genes (DEGs) were obtained in datasets of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2 and myocardial tissues from heart failure patients. Further GO and KEGG pathway analysis, protein–protein interaction (PPI) network construction, hub genes identification, immune microenvironment analysis, and drug candidate predication were performed. Then, an isoproterenol-stimulated myocardial hypertrophy cell model and a transverse aortic constriction-induced mouse heart failure model were employed to validate the expression of hub genes. Results A total of 315 up-regulated and 78 down-regulated common DEGs were identified. Functional enrichment analysis revealed mitochondrial metabolic disorders and extensive immune inflammation as the most prominent shared features of COVID-19 and cardiovascular diseases. Then, hub DEGs, as well as hub immune-related and mitochondria-related DEGs, were screened. Additionally, nine potential therapeutic agents for COVID-19-related cardiovascular diseases were proposed. Furthermore, the expression patterns of most of the hub genes related to cardiovascular diseases in the validation dataset along with cellular and mouse myocardial damage models, were consistent with the findings of bioinformatics analysis. Conclusions The study unveiled the molecular networks and signaling pathways connecting COVID-19 and cardiovascular diseases, which may provide novel targets for intervention of COVID-19-related cardiovascular diseases.

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“…Like many other viruses, SARS-CoV-2 affects the immunometabolic system, causing a Warburg-like shift [5]. According to bioinformatics analysis [43], the main molecular mechanism of cardiac injury in SARS-CoV-2 infection is mitochondrial dysfunction. Our results revealed that an acute infection by virus epitope suppressed mitochondrial respiration in primary cardiomyocytes, resulting in decreased ATP production and redistributed energy phenotype to more glycolytic.…”

Section: Discussionmentioning

confidence: 99%

The Effect of SARS-CoV-2 Spike Protein RBD-Epitope on Immunometabolic State and Functional Performance of Cultured Primary Cardiomyocytes Subjected to Hypoxia and Reoxygenation

Keturakis,

Narauskaitė,

Balion

et al. 2023

IJMS

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Cardio complications such as arrhythmias and myocardial damage are common in COVID-19 patients. SARS-CoV-2 interacts with the cardiovascular system primarily via the ACE2 receptor. Cardiomyocyte damage in SARS-CoV-2 infection may stem from inflammation, hypoxia–reoxygenation injury, and direct toxicity; however, the precise mechanisms are unclear. In this study, we simulated hypoxia–reoxygenation conditions commonly seen in SARS-CoV-2-infected patients and studied the impact of the SARS-CoV-2 spike protein RBD-epitope on primary rat cardiomyocytes to gain insight into the potential mechanisms underlying COVID-19-related cardiac complications. Cell metabolic activity was evaluated with PrestoBlueTM. Gene expression of proinflammatory markers was measured by qRT-PCR and their secretion was quantified by Luminex assay. Cardiomyocyte contractility was analysed using the Myocyter plugin of ImageJ. Mitochondrial respiration was determined through Seahorse Mito Stress Test. In hypoxia–reoxygenation conditions, treatment of the SARS-CoV-2 spike RBD-epitope reduced the metabolic activity of primary cardiomyocytes, upregulated Il1β and Cxcl1 expression, and elevated GM-CSF and CCL2 cytokines secretion. Contraction time increased, while amplitude and beating frequency decreased. Acute treatment with a virus RBD-epitope inhibited mitochondrial respiration and lowered ATP production. Under ischaemia-reperfusion, the SARS-CoV-2 RBD-epitope induces cardiomyocyte injury linked to impaired mitochondrial activity.

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The molecular mechanism of cardiac injury in SARS-CoV-2 infection: Focus on mitochondrial dysfunction

Cited by 10 publications

References 38 publications

Decoding HiPSC-CM’s Response to SARS-CoV-2: mapping the molecular landscape of cardiac injury

Decoding HiPSC-CM’s Response to SARS-CoV-2: mapping the molecular landscape of cardiac injury

Landscape of molecular crosstalk between SARS-CoV-2 infection and cardiovascular diseases: emphasis on mitochondrial dysfunction and immune-inflammation

The Effect of SARS-CoV-2 Spike Protein RBD-Epitope on Immunometabolic State and Functional Performance of Cultured Primary Cardiomyocytes Subjected to Hypoxia and Reoxygenation

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