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      Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte

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          Abstract

          Rationale

          About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance.

          Objective

          To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes.

          Methods and results

          We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization.

          Conclusions

          The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12933-021-01286-7.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
          Article 0 comments Cited 9650 times – based on 0 reviews     Review now
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            Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

            Nanshan Chen, Min Zhou, Xuan Dong … (2022)
            Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.
            Article 0 comments Cited 9341 times – based on 0 reviews     Review now
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              Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

              Victor M Corman, Olfert Landt, Marco Kaiser … (2020)
              Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
              Article 0 comments Cited 3498 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Celestino Sardu:
                ORCID: http://orcid.org/0000-0001-5099-3790
                celestino.sardu@unicampania.it
                Journal
                Journal ID (nlm-ta): Cardiovasc Diabetol
                Journal ID (iso-abbrev): Cardiovasc Diabetol
                Title: Cardiovascular Diabetology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1475-2840
                Publication date (Electronic): 7 May 2021
                Publication date PMC-release: 7 May 2021
                Publication date Collection: 2021
                Volume: 20
                Electronic Location Identifier: 99
                Affiliations
                [1 ]Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
                [2 ]Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138 Naples, Italy
                [3 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Department of Experimental Medicine, , University of Campania “Luigi Vanvitelli”, ; Naples, Italy
                [4 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Department of Cardio-Thoracic Sciences, , University of Campania “Luigi Vanvitelli”, ; Naples, Italy
                [5 ]GRID grid.416052.4, ISNI 0000 0004 1755 4122, Unit of Cardiac Surgery and Transplants, , AORN Ospedali dei Colli-Monaldi Hospital, ; 80131 Naples, Italy
                [6 ]Department of Experimental Medicine Forensic Pathology Service, University of Campania L. Vanvitelli, Naples, Italy
                [7 ]Department of Forensic, Evaluative and Necroscopic Medicine, ASL Napoli 2 NORD, Naples, Italy
                [8 ]Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy
                [9 ]GRID grid.445670.4, ISNI 0000 0001 2203 5595, Institute of Life Science, , Vasile Goldis Western University, ; Arad, Romania
                [10 ]GRID grid.477084.8, ISNI 0000 0004 1787 3414, Mediterranea Cardiocentro, ; Naples, Italy
                Author information
                http://orcid.org/0000-0001-5099-3790
                Article
                Publisher ID: 1286
                DOI: 10.1186/s12933-021-01286-7
                PMC ID: 8104461
                PubMed ID: 33962629
                SO-VID: 694e0056-cade-41df-8a07-61313150ea9a
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 19 March 2021
                Date accepted : 23 April 2021
                Categories
                Subject: Original Investigation
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: covid-19,sars-cov-2,cardiomyocyte,diabetes,heart,ace2
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: covid-19, sars-cov-2, cardiomyocyte, diabetes, heart, ace2

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