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Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte.
D'Onofrio, Nunzia; Scisciola, Lucia; Sardu, Celestino; Trotta, Maria Consiglia; De Feo, Marisa; Maiello, Ciro; Mascolo, Pasquale; De Micco, Francesco; Turriziani, Fabrizio; Municinò, Emilia; Monetti, Pasquale; Lombardi, Antonio; Napolitano, Maria Gaetana; Marino, Federica Zito; Ronchi, Andrea; Grimaldi, Vincenzo; Hermenean, Anca; Rizzo, Maria Rosaria; Barbieri, Michelangela; Franco, Renato; Campobasso, Carlo Pietro; Napoli, Claudio; Municinò, Maurizio; Paolisso, Giuseppe; Balestrieri, Maria Luisa; Marfella, Raffaele.
  • D'Onofrio N; Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy.
  • Scisciola L; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Sardu C; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy. celestino.sardu@unicampania.it.
  • Trotta MC; Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • De Feo M; Department of Cardio-Thoracic Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • Maiello C; Unit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi Hospital, 80131, Naples, Italy.
  • Mascolo P; Department of Experimental Medicine Forensic Pathology Service, University of Campania L. Vanvitelli, Naples, Italy.
  • De Micco F; Department of Experimental Medicine Forensic Pathology Service, University of Campania L. Vanvitelli, Naples, Italy.
  • Turriziani F; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Municinò E; Department of Forensic, Evaluative and Necroscopic Medicine, ASL Napoli 2 NORD, Naples, Italy.
  • Monetti P; Department of Forensic, Evaluative and Necroscopic Medicine, ASL Napoli 2 NORD, Naples, Italy.
  • Lombardi A; Department of Forensic, Evaluative and Necroscopic Medicine, ASL Napoli 2 NORD, Naples, Italy.
  • Napolitano MG; Department of Forensic, Evaluative and Necroscopic Medicine, ASL Napoli 2 NORD, Naples, Italy.
  • Marino FZ; Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy.
  • Ronchi A; Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy.
  • Grimaldi V; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Hermenean A; Institute of Life Science, Vasile Goldis Western University, Arad, Romania.
  • Rizzo MR; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Barbieri M; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Franco R; Department of Mental and Physical Health and Preventive Medicine, University of Campania L. Vanvitelli, Naples, Italy.
  • Campobasso CP; Department of Experimental Medicine Forensic Pathology Service, University of Campania L. Vanvitelli, Naples, Italy.
  • Napoli C; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Municinò M; Department of Forensic, Evaluative and Necroscopic Medicine, ASL Napoli 2 NORD, Naples, Italy.
  • Paolisso G; Department of Advanced Medical and Surgical Sciences, University of Campania L. Vanvitelli, Piazza Miraglia, 2, 80138, Naples, Italy.
  • Balestrieri ML; Mediterranea Cardiocentro, Naples, Italy.
  • Marfella R; Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy.
Cardiovasc Diabetol ; 20(1): 99, 2021 05 07.
Article in English | MEDLINE | ID: covidwho-1219133
Semantic information from SemMedBD (by NLM)
1. Myocyte LOCATION_OF C1422064|59272
Subject
Myocyte
Predicate
LOCATION_OF
Object
C1422064|59272
2. ACE2 gene|ACE2 ASSOCIATED_WITH Diabetes
Subject
ACE2 gene|ACE2
Predicate
ASSOCIATED_WITH
Object
Diabetes
3. COVID-19 PROCESS_OF hospitalized patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
hospitalized patients
4. Diabetes Mellitus PROCESS_OF hospitalized patients
Subject
Diabetes Mellitus
Predicate
PROCESS_OF
Object
hospitalized patients
5. Diabetes Mellitus PROCESS_OF Patients
Subject
Diabetes Mellitus
Predicate
PROCESS_OF
Object
Patients
6. Heart LOCATION_OF Autopsy
Subject
Heart
Predicate
LOCATION_OF
Object
Autopsy
7. Myocyte LOCATION_OF C5203676
Subject
Myocyte
Predicate
LOCATION_OF
Object
C5203676
8. TMPRSS2 gene|TMPRSS2 INTERACTS_WITH Myocyte
Subject
TMPRSS2 gene|TMPRSS2
Predicate
INTERACTS_WITH
Object
Myocyte
9. ACE2 gene|ACE2 INTERACTS_WITH Myocyte
Subject
ACE2 gene|ACE2
Predicate
INTERACTS_WITH
Object
Myocyte
10. ACE2 gene|ACE2 PART_OF Homo sapiens
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
Homo sapiens
11. ACE2 gene|ACE2 INTERACTS_WITH spike protei
Subject
ACE2 gene|ACE2
Predicate
INTERACTS_WITH
Object
spike protei
12. Myocyte LOCATION_OF C0004398
Subject
Myocyte
Predicate
LOCATION_OF
Object
C0004398
13. Myocyte LOCATION_OF C1336641|7113
Subject
Myocyte
Predicate
LOCATION_OF
Object
C1336641|7113
14. glucose AFFECTS protein complex oligomerization
Subject
glucose
Predicate
AFFECTS
Object
protein complex oligomerization
15. Up-Regulation (Physiology) PROCESS_OF Myocyte
Subject
Up-Regulation (Physiology)
Predicate
PROCESS_OF
Object
Myocyte
16. Up-Regulation (Physiology) PROCESS_OF Patients
Subject
Up-Regulation (Physiology)
Predicate
PROCESS_OF
Object
Patients
17. Myocytes, Cardiac LOCATION_OF ACE2 gene|ACE2
Subject
Myocytes, Cardiac
Predicate
LOCATION_OF
Object
ACE2 gene|ACE2
18. ACE2 gene|ACE2 ASSOCIATED_WITH Diabetes
Subject
ACE2 gene|ACE2
Predicate
ASSOCIATED_WITH
Object
Diabetes
19. COVID-19 PROCESS_OF hospitalized patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
hospitalized patients
20. Diabetes Mellitus PROCESS_OF hospitalized patients
Subject
Diabetes Mellitus
Predicate
PROCESS_OF
Object
hospitalized patients
21. Diabetes Mellitus PROCESS_OF Patients
Subject
Diabetes Mellitus
Predicate
PROCESS_OF
Object
Patients
22. Heart LOCATION_OF Autopsy
Subject
Heart
Predicate
LOCATION_OF
Object
Autopsy
23. Myocytes, Cardiac LOCATION_OF 2019 novel coronavirus
Subject
Myocytes, Cardiac
Predicate
LOCATION_OF
Object
2019 novel coronavirus
24. TMPRSS2 gene|TMPRSS2 INTERACTS_WITH Myocytes, Cardiac
Subject
TMPRSS2 gene|TMPRSS2
Predicate
INTERACTS_WITH
Object
Myocytes, Cardiac
25. ACE2 gene|ACE2 INTERACTS_WITH Myocytes, Cardiac
Subject
ACE2 gene|ACE2
Predicate
INTERACTS_WITH
Object
Myocytes, Cardiac
26. ACE2 gene|ACE2 PART_OF Homo sapiens
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
Homo sapiens
27. ACE2 gene|ACE2 INTERACTS_WITH spike protein, SARS-CoV-2
Subject
ACE2 gene|ACE2
Predicate
INTERACTS_WITH
Object
spike protein, SARS-CoV-2
28. Myocytes, Cardiac LOCATION_OF Autopsy
Subject
Myocytes, Cardiac
Predicate
LOCATION_OF
Object
Autopsy
29. Myocytes, Cardiac LOCATION_OF TMPRSS2 gene|TMPRSS2
Subject
Myocytes, Cardiac
Predicate
LOCATION_OF
Object
TMPRSS2 gene|TMPRSS2
30. glucose AFFECTS protein complex oligomerization
Subject
glucose
Predicate
AFFECTS
Object
protein complex oligomerization
31. Up-Regulation (Physiology) PROCESS_OF Myocytes, Cardiac
Subject
Up-Regulation (Physiology)
Predicate
PROCESS_OF
Object
Myocytes, Cardiac
32. Up-Regulation (Physiology) PROCESS_OF Patients
Subject
Up-Regulation (Physiology)
Predicate
PROCESS_OF
Object
Patients
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Myocytes, Cardiac / Diabetes Mellitus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Type of study: Etiology study / Incidence study / Observational study / Risk factors Limits: Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Journal: Cardiovasc Diabetol Journal subject: Vascular Diseases / Cardiology / Endocrinology Year: 2021 Document Type: Article Affiliation country: S12933-021-01286-7

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Myocytes, Cardiac / Diabetes Mellitus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Type of study: Etiology study / Incidence study / Observational study / Risk factors Limits: Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: English Journal: Cardiovasc Diabetol Journal subject: Vascular Diseases / Cardiology / Endocrinology Year: 2021 Document Type: Article Affiliation country: S12933-021-01286-7