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Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients.
Zamai, Loris.
  • Zamai L; Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
Cells ; 10(3)2021 02 27.
Article in English | MEDLINE | ID: covidwho-1122409
Semantic information from SemMedBD (by NLM)
1. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
2. Chelating Agents TREATS COVID-19
Subject
Chelating Agents
Predicate
TREATS
Object
COVID-19
3. Chelating Agents TREATS Patients
Subject
Chelating Agents
Predicate
TREATS
Object
Patients
4. ADAM17 Protein|ADAM17 STIMULATES ACE2 gene|ACE2
Subject
ADAM17 Protein|ADAM17
Predicate
STIMULATES
Object
ACE2 gene|ACE2
5. ADAM17 Protein|ADAM17 AFFECTS Up-Regulation (Physiology)
Subject
ADAM17 Protein|ADAM17
Predicate
AFFECTS
Object
Up-Regulation (Physiology)
6. spike glycoprotei INTERACTS_WITH C1422064|59272
Subject
spike glycoprotei
Predicate
INTERACTS_WITH
Object
C1422064|59272
7. COVID-19 AFFECTS Excessive activity
Subject
COVID-19
Predicate
AFFECTS
Object
Excessive activity
8. Up-Regulation (Physiology) PROCESS_OF Patients
Subject
Up-Regulation (Physiology)
Predicate
PROCESS_OF
Object
Patients
9. loops TREATS COVID-19
Subject
loops
Predicate
TREATS
Object
COVID-19
10. Citrates PREVENTS COVID-19
Subject
Citrates
Predicate
PREVENTS
Object
COVID-19
11. edetic acid PREVENTS COVID-19
Subject
edetic acid
Predicate
PREVENTS
Object
COVID-19
12. Anticoagulants INHIBITS Metalloproteases
Subject
Anticoagulants
Predicate
INHIBITS
Object
Metalloproteases
13. edetic acid TREATS COVID-19
Subject
edetic acid
Predicate
TREATS
Object
COVID-19
14. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
15. Chelating Agents TREATS COVID-19
Subject
Chelating Agents
Predicate
TREATS
Object
COVID-19
16. Chelating Agents TREATS Patients
Subject
Chelating Agents
Predicate
TREATS
Object
Patients
17. ADAM17 Protein|ADAM17 STIMULATES ACE2 gene|ACE2
Subject
ADAM17 Protein|ADAM17
Predicate
STIMULATES
Object
ACE2 gene|ACE2
18. ADAM17 Protein|ADAM17 AFFECTS Up-Regulation (Physiology)
Subject
ADAM17 Protein|ADAM17
Predicate
AFFECTS
Object
Up-Regulation (Physiology)
19. spike glycoprotein, SARS-CoV INTERACTS_WITH ACE2 gene|ACE2
Subject
spike glycoprotein, SARS-CoV
Predicate
INTERACTS_WITH
Object
ACE2 gene|ACE2
20. COVID-19 AFFECTS Excessive activity
Subject
COVID-19
Predicate
AFFECTS
Object
Excessive activity
21. Up-Regulation (Physiology) PROCESS_OF Patients
Subject
Up-Regulation (Physiology)
Predicate
PROCESS_OF
Object
Patients
22. loops TREATS COVID-19
Subject
loops
Predicate
TREATS
Object
COVID-19
23. Citrates PREVENTS COVID-19
Subject
Citrates
Predicate
PREVENTS
Object
COVID-19
24. edetic acid PREVENTS COVID-19
Subject
edetic acid
Predicate
PREVENTS
Object
COVID-19
25. Anticoagulants INHIBITS Metalloproteases
Subject
Anticoagulants
Predicate
INHIBITS
Object
Metalloproteases
26. edetic acid TREATS COVID-19
Subject
edetic acid
Predicate
TREATS
Object
COVID-19
ABSTRACT
The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to "clinical" manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Renin-Angiotensin System / Zinc / Chelating Agents / Edetic Acid / Citric Acid / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Year: 2021 Document Type: Article Affiliation country: Cells10030506

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Renin-Angiotensin System / Zinc / Chelating Agents / Edetic Acid / Citric Acid / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Year: 2021 Document Type: Article Affiliation country: Cells10030506