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Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes
Published on: May 25, 2022
Ectopic expression of SARS-CoV-2 S and ORF-9B proteins alters metabolic profiles and impairs contractile function in
Peng Zhang1, Yu Liu2, Chunfeng Li3
1Department of Biological Sciences, Clemson University, Clemson, SC, United States.
Abstract:
Coronavirus disease 2019 (COVID-19) is associated with adverse impacts in the cardiovascular system, but the mechanisms driving this response remain unclear. In this study, we conducted "pseudoviral infection" of SARS-CoV-2 subunits to evaluate their toxic effects in cardiomyocytes (CMs), that were derived from human induced pluripotent stem cells (hiPSCs). We found that the ectopic expression of S and ORF-9B subunits significantly impaired the contractile function and altered the metabolic profiles in human cardiomyocytes. Further mechanistic study has shown that the mitochondrial oxidative phosphorylation (OXPHOS), membrane potential, and ATP production were significantly decreased two days after the overexpression of S and ORF-9B subunits, while S subunits induced higher level of reactive oxygen species (ROS). Two weeks after overexpression, glycolysis was elevated in the ORF-9B group. Based on the transcriptomic analysis, both S and ORF-9B subunits dysregulated signaling pathways associated with metabolism and cardiomyopathy, including upregulated genes involved in HIF-signaling and downregulated genes involved in cholesterol biosynthetic processes. The ORF-9B subunit also enhanced glycolysis in the CMs. Our results collectively provide an insight into the molecular mechanisms underlying SARS-CoV-2 subunits-induced metabolic alterations and cardiac dysfunctions in the hearts of COVID-19 patients.
Insights
The SARS-CoV-2 S and ORF-9B viral subunits impair heart cell function and metabolism. This study reveals mechanisms of COVID-19 cardiac complications, offering insights into viral impacts on the cardiovascular system.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Virology
Background:
- Coronavirus disease 2019 (COVID-19) presents cardiovascular complications.
- The precise molecular mechanisms underlying these cardiac impacts remain largely unknown.
Purpose of the Study:
- To investigate the toxic effects of SARS-CoV-2 subunits on human cardiomyocytes.
- To elucidate the molecular mechanisms of COVID-19-associated cardiac dysfunction and metabolic alterations.
Main Methods:
- Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for pseudoviral infection with SARS-CoV-2 subunits.
- Assessed cellular function, metabolic profiles, mitochondrial activity, and gene expression.
- Performed transcriptomic analysis to identify dysregulated pathways.
Main Results:
- Ectopic expression of S and ORF-9B subunits impaired cardiomyocyte contractile function and altered metabolic profiles.
- Mitochondrial oxidative phosphorylation, membrane potential, and ATP production decreased; reactive oxygen species (ROS) increased with S subunit expression.
- ORF-9B subunit overexpression led to elevated glycolysis and dysregulated metabolism-related signaling pathways, including HIF-signaling.
Conclusions:
- SARS-CoV-2 S and ORF-9B subunits induce significant metabolic alterations and cardiac dysfunction in human cardiomyocytes.
- These findings provide critical insights into the molecular basis of cardiovascular complications in COVID-19 patients.
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