tetano
Editor, Senior Moderator
Stem Cell Reports
. 2022 Feb 1;S2213-6711(22)00058-3.
doi: 10.1016/j.stemcr.2022.01.014. Online ahead of print.
Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes
Juli Liu[SUP] 1 [/SUP], Yucheng Zhang[SUP] 2 [/SUP], Lei Han[SUP] 1 [/SUP], Shuai Guo[SUP] 1 [/SUP], Shiyong Wu[SUP] 1 [/SUP], Emma Helen Doud[SUP] 3 [/SUP], Cheng Wang[SUP] 1 [/SUP], Hanying Chen[SUP] 2 [/SUP], Michael Rubart-von der Lohe[SUP] 1 [/SUP], Jun Wan[SUP] 2 [/SUP], Lei Yang[SUP] 4 [/SUP]
Affiliations
Abstract
Patients with coronavirus disease 2019 (COVID-19) commonly have manifestations of heart disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 27 proteins. Currently, SARS-CoV-2 gene-induced abnormalities of human heart muscle cells remain elusive. Here, we comprehensively characterized the detrimental effects of a SARS-CoV-2 gene, Orf9c, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) by preforming multi-omic analyses. Transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with Orf9c overexpression (Orf9c[SUP]OE[/SUP]) identified concordantly up-regulated genes enriched into stress-related apoptosis and inflammation signaling pathways, and down-regulated CM functional genes. Proteomic analysis revealed enhanced expressions of apoptotic factors, whereas reduced protein factors for ATP synthesis by Orf9c[SUP]OE[/SUP]. Orf9c[SUP]OE[/SUP] significantly reduced cellular ATP level, induced apoptosis, and caused electrical dysfunctions of hPSC-CMs. Finally, drugs approved by the U.S. Food and Drug Administration, namely, ivermectin and meclizine, restored ATP levels and ameliorated CM death and functional abnormalities of Orf9c[SUP]OE[/SUP] hPSC-CMs. Overall, we defined the molecular mechanisms underlying the detrimental impacts of Orf9c on hPSC-CMs and explored potentially therapeutic approaches to ameliorate Orf9c-induced cardiac injury and abnormalities.
Keywords: Orf9c; SARS-CoV-2; apoptosis; cardiac dysfunction; cardiomyocyte; human pluripotent stem cell; ivermectin; meclizine.
. 2022 Feb 1;S2213-6711(22)00058-3.
doi: 10.1016/j.stemcr.2022.01.014. Online ahead of print.
Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes
Juli Liu[SUP] 1 [/SUP], Yucheng Zhang[SUP] 2 [/SUP], Lei Han[SUP] 1 [/SUP], Shuai Guo[SUP] 1 [/SUP], Shiyong Wu[SUP] 1 [/SUP], Emma Helen Doud[SUP] 3 [/SUP], Cheng Wang[SUP] 1 [/SUP], Hanying Chen[SUP] 2 [/SUP], Michael Rubart-von der Lohe[SUP] 1 [/SUP], Jun Wan[SUP] 2 [/SUP], Lei Yang[SUP] 4 [/SUP]
Affiliations
- PMID: 35180394
- PMCID: PMC8851680
- DOI: 10.1016/j.stemcr.2022.01.014
Abstract
Patients with coronavirus disease 2019 (COVID-19) commonly have manifestations of heart disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 27 proteins. Currently, SARS-CoV-2 gene-induced abnormalities of human heart muscle cells remain elusive. Here, we comprehensively characterized the detrimental effects of a SARS-CoV-2 gene, Orf9c, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) by preforming multi-omic analyses. Transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with Orf9c overexpression (Orf9c[SUP]OE[/SUP]) identified concordantly up-regulated genes enriched into stress-related apoptosis and inflammation signaling pathways, and down-regulated CM functional genes. Proteomic analysis revealed enhanced expressions of apoptotic factors, whereas reduced protein factors for ATP synthesis by Orf9c[SUP]OE[/SUP]. Orf9c[SUP]OE[/SUP] significantly reduced cellular ATP level, induced apoptosis, and caused electrical dysfunctions of hPSC-CMs. Finally, drugs approved by the U.S. Food and Drug Administration, namely, ivermectin and meclizine, restored ATP levels and ameliorated CM death and functional abnormalities of Orf9c[SUP]OE[/SUP] hPSC-CMs. Overall, we defined the molecular mechanisms underlying the detrimental impacts of Orf9c on hPSC-CMs and explored potentially therapeutic approaches to ameliorate Orf9c-induced cardiac injury and abnormalities.
Keywords: Orf9c; SARS-CoV-2; apoptosis; cardiac dysfunction; cardiomyocyte; human pluripotent stem cell; ivermectin; meclizine.