SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2

Lei, Yuyang; Zhang, Jiao; Schiavon, Cara R.; He, Ming; Chen, Lili; Shen, Hui; Zhang, Yichi; Yin, Qian; Cho, Yoshitake; Andrade, Leonardo R.; Shadel, Gerald S.; Hepokoski, Mark; Lei, Ting; Wang, Hongliang; Zhang, Jin; Yuan, Jason X.‐J.; Malhotra, Atul; Manor, Uri; Wang, Shengpeng; Yuan, Zhao; Shyy, John Y.‐J.

doi:10.1161/circresaha.121.318902

Cited by 395 publications

(442 citation statements)

References 5 publications

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“…As a homologue of ACE, ACE2 antagonizes ACE function by converting AngII to Ang 1-7 (anti-inflammatory and vasodilatory). Since CoV-2-S engages ACE2 to mediate virus entry, it may harm CMs by destabilizing ACE2 (Chen et al, 2020a), as it does in endothelial cells (Lei et al, 2021). Nevertheless, emerging evidence suggests that CoV-2-S may also harm the heart through ACE2-independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In hospitalized COVID-19 patients, cardiac injury portends higher mortality rate (Guo et al, 2020;Mitrani et al, 2020) and poorer prognosis (Fayol et al, 2021). In recovered COVID-19 patients who experienced myocardial injury, cardiac function abnormalities have been observed (Fayol et al, 2021;Wang et al, 2021), raising the concern as to whether CoV-2 infection causes permanent cardiac damages and leads to chronic cardiac complications (Yancy and Fonarow, 2020;Shchendrygina et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…ACE2 is a crucial enzyme of the renin angiotensin system (RAS) that maintains blood pressure homeostasis (Teerlink, 1996), and is critical in modulating cardiac hypertrophy through Angiotensin 2 regulation. In COVID-19 patients, CoV-2-S may impair cardiac ACE2 function and expression, as it does in endothelial cells (Lei et al, 2021), therefore leading to cardiac injury (Chen et al, 2020a). Alternatively, it may also damage the heart through ACE2-independent mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice

et al. 2021

Preprint

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Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 Spike glycoprotein (CoV-2-S) not only engages ACE2 to mediate virus infection, but also directly impairs endothelial function and can trigger innate immune responses in cultured murine macrophages. Here we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor that responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated a construct that expresses membrane-localized CoV-2-S1 (S1-TM). AAV9-mediated, selective expression of the S1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. Since CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S, and suggests that the circulating CoV-2-S1 is a TLR4-recognizable alarmin that may harm the CMs by triggering their innate immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice

et al. 2021

Preprint

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“…So far, great efforts have been dedicated to successfully developing the spike-based vaccines to combat the pandemic. Nevertheless, many challenges still remain to completely terminate the pandemic, which include the rapidly-emerging antibody-resistance variants (24), the adverse effects of the spike protein (25) and even its antibody (26). Most seriously, SARS-CoV-2 spike protein has been identified to provoke antibody-dependent enhancement (ADE) of infection (27,28) while its RNA fragments were shown to get integrated into human genome (29).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS

Song

Dang

2021

Preprint

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Great efforts have led to successfully developing the spike-based vaccines but challenges still exist to completely terminate the SARS-CoV-2 pandemic. SARS-CoV-2 nucleocapsid (N) protein plays the essential roles in almost all key steps of the viral life cycle, thus representing a top drug target. Almost all key functions of N protein including liquid-liquid phase separation (LLPS) depend on its capacity in interacting with nucleic acids. Therefore, only the variants with their N proteins functional in binding nucleic acids might survive and spread in evolution and indeed, the residues critical for binding nucleic acids are highly conserved. Very recently, hydroxychloroquine (HCQ) was shown to prevent the transmission in a large-scale clinical study in Singapore but so far, no specific SARS-CoV-2 protein was experimentally identified to be targeted by HCQ. Here by NMR, we unambiguously decode that HCQ specifically binds NTD and CTD of SARS- CoV-2 N protein with Kd of 112.1 and 57.1 μM respectively to inhibit their interaction with nucleic acid, as well as to disrupt LLPS essential for the viral life cycle. Most importantly, HCQ-binding residues are identical in SARS-CoV-2 variants and therefore HCQ is likely effective to them all. The results not only provide a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also renders HCQ to be the first known drug capable of targeting LLPS. Furthermore, the unique structure of the HCQ-CTD complex decodes a promising strategy for further design of better anti-SARS-CoV-2 drugs from HCQ. Therefore, HCQ is a promising candidate to help terminate the pandemic.

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“…Indeed, endothelial cells are efficiently transduced upon intramuscular injection [ 51 ]. Transduced endothelial cells might be directly damaged by the spike protein that they synthesize, as suggested by in vitro and in vivo observations [ 52 , 53 ]. Furthermore, endothelial cells might expose the spike protein on their luminal side, possibly bound to PG of the glycocalyx as heparan sulfate PGs were shown to be attachment factors for the spike protein [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

Thrombotic thrombocytopenia associated with COVID-19 infection or vaccination: Possible paths to platelet factor 4 autoimmunity

Goldman¹,

Hermans

2021

PLoS Med

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SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2

Cited by 395 publications

References 5 publications

Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice

Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice

Structural basis of anti-SARS-CoV-2 activity of HCQ: specific binding to N protein to disrupt its interaction with nucleic acids and LLPS

Thrombotic thrombocytopenia associated with COVID-19 infection or vaccination: Possible paths to platelet factor 4 autoimmunity

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