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SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular Ca homeostasis & impairs pulmonary vascular endothelial cells, 2023, Yang+

Discussion in 'Long Covid research' started by SNT Gatchaman, Jul 15, 2023.

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  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells
    Yang, Kai; Liu, Shiyun; Yan, Han; Lu, Wenju; Shan, Xiaoqian; Chen, Haixia; Bao, Changlei; Feng, Huazhuo; Liao, Jing; Liang, Shuxin; Xu, Lei; Tang, Haiyang; Yuan, Jason X.-J.; Zhong, Nanshan; Wang, Jian

    Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium.

    Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis. These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+]i. Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD.

    In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+]i through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+]i axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases.

    Link | PDF (Nature Signal Transduction and Targeted Therapy)
     
    SNT Gatchaman, Jul 15, 2023
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  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Screenshot 2023-07-16 at 8.34.52 AM Large.jpeg
     
    SNT Gatchaman, Jul 15, 2023
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  3. Hutan

    Hutan Moderator Staff Member

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    Interesting, SNT, especially in the context of the NCNED suggestions of TRP channels having problems in ME/CFS and the findings and symptoms of ME/CFS that seem to fit with endothelial dysfunction. I haven't read this study yet. From the abstract, it looks as though they are suggesting that the pathogenic protein leaves calcium channels stuck in the 'on' position, resulting in increased intra-cellular calcium levels and cell death. Do I have that right?


    I had a question about how long endothelial cells live for, and found this answer online:
    So, if an endothelial cell had its calcium channels unregulated by exposure to a pathogen, it could cause problems for a long time. Presumably at some point though the affected endothelial cells would die (perhaps earlier rather than later if they are sick?) and healthy new ones would take their place? So, for this to be an answer to Long Covid or ME/CFS, there would need to be a mechanism whereby the damaged cells are replaced with new, also damaged, cells. If there was a residual infection in the bone marrow, could that produce damaged new endothelial cells before they transit to the endothelium? Or, if there was a residual infection somewhere else, could periodic sub-clinical flares produce pathogenic proteins that damage healthy endothelial cells?

    Is the spike protein in SARS-CoV-2 unique in its capacity to bind to ACE2? Do we have any evidence that ACE2 is targeted by other pathogens that are implicated in ME/CFS onset?
     
    Hutan, Jul 15, 2023
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  4. Hutan

    Hutan Moderator Staff Member

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    It seems that viruses in general target host cell calcium channels in various ways - see here:
    Host Calcium Channels and Pumps in Viral Infections, 2020, Chen et al
     
    Hutan, Jul 15, 2023
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