Thematic Article
Volume 9 Issue 4 - 2021
Renin-Angiotensin System, SARS-CoV-2 and Hypotheses about Adverse Effects Following Vaccination
Paolo Bellavite*
Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy
*Corresponding Author: Paolo Bellavite, Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.
Received: March 15, 2021; Published: March 30, 2021


Coronavirus disease 2019 (COVID-19) affects the lungs but also the cardiovascular system, especially since the spike protein of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) uses the angiotensin-converting enzyme 2 (ACE2), existing on the membrane of many cell species, as a receptor. This connection has consequences on the renin-angiotensin system, arterial pressure and coagulation. An imbalance of blood pressure control, of coagulation and platelet functions, and of the kinin-kallikrein system may occur in natural disease but is also partly reflected in some possible negative consequences following vaccination. Knowledge of these mechanisms could help to identify the subjects most at risk of complications and to correctly carry out the causality assessment of adverse events.

Keywords: COVID-19; Renin-Angiotensin System; ACE2; Vaccination; Spike Protein; Arterial Pressure; Kinine System; Immunopharmacology; Thrombosis


  1. Alifano M., et al. “Renin-angiotensin system at the heart of COVID-19 pandemic”. Biochimie 174 (2020): 30-33.
  2. Verdecchia P., et al. “The pivotal link between ACE2 deficiency and SARS-CoV-2 infection”. European Journal of Internal Medicine 76 (2020): 14-20.
  3. Barrera FJ., et al. “Prevalence of Diabetes and Hypertension and Their Associated Risks for Poor Outcomes in Covid-19 Patients”. Journal of the Endocrine Society 9 (2020): bvaa102.
  4. Puliyel J and Naik P. “Revised World Health Organization (WHO)'s causality assessment of adverse events following immunization-a critique”. F1000 Research 7 (2018): 243.
  5. Bellavite P. “Causality assessment of adverse events following immunization: the problem of multifactorial pathology”. F1000 Research 9 (2020): 170.
  6. Bellavite P and Donzelli A. “Adverse events following measles-mumps-rubella-varicella vaccine: an independent perspective on Italian pharmacovigilance data”. F1000 Research 9 (2020): 1176.
  7. Du F., et al. “COVID-19: the role of excessive cytokine release and potential ACE2 down-regulation in promoting hypercoagulable state associated with severe illness”. The Journal of Thrombosis and Thrombolysis (2020): 1-17.
  8. Lu J and Sun PD. “High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity”. Journal of Biological Chemistry52 (2020): 18579-18588.
  9. Ramlall V., et al. “Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection”. Nature Medicine 10 (2020): 1609-1615.
  10. Liu PP., et al. “The Science Underlying COVID-19: Implications for the Cardiovascular System”. Circulation1 (2020): 68-78.
  11. Oz M and Lorke DE. “Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury”. Biomedicine and Pharmacotherapy 136 (2021): 111193.
  12. Davidson AM., et al. “Interaction of SARS-CoV-2 and Other Coronavirus With ACE (Angiotensin-Converting Enzyme)-2 as Their Main Receptor: Therapeutic Implications”. Hypertension5 (2020): 1339-1349.
  13. Pang J., et al. “Friend or Foe? ACE2 inhibitors and GLP-1R agonists in COVID-19 treatment”. Obesity Medicine (2021): 100312.
  14. Albashir AAD. “Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors and Coronavirus Disease 2019 (COVID-19)”. Southern Medical Journal 1 (2021): 51-56.
  15. Costa LB., et al. “Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System”. Frontiers in Cell and Developmental Biology 8 (2020): 559841.
  16. Rahman MM., et al. “Potential detrimental role of soluble ACE2 in severe COVID-19 comorbid patients”. Reviews in Medical Virology (2021).
  17. Rojas A., et al. “SARS-CoV-2-mediated inflammatory response in lungs: should we look at RAGE?” Inflammation Research 7 (2020): 641-643.
  18. Kaplan AP and Joseph K. “Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway”. Advances in Immunology 121 (2014): 41-89.
  19. McCarthy CG., et al. “A new storm on the horizon in COVID-19: Bradykinin-induced vascular complications”. Vascular Pharmacology (2020): 106826.
  20. Garvin MR., et al. “A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm”. Elife (2020): 9.
  21. Sidarta-Oliveira D., et al. “SARS-CoV-2 receptor is co-expressed with elements of the kinin-kallikrein, renin-angiotensin and coagulation systems in alveolar cells”. Scientific Reports1 (2020): 19522.
  22. Lippi G., et al. “Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19)”. Annals of Clinical Biochemistry3 (2020): 262-265.
  23. Cervellin G., et al. “Serum potassium levels inversely correlate with D-dimer in patients with acute-onset atrial fibrillation”. Arquivos Brasileiros de Cardiologia 3 (2015): 181-184.
  24. Roche JA and Roche R. “A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications”. The FASEB Journal6 (2020): 7265-7269.
  25. Muslim S., et al. “Treatment Options Available for COVID-19 and an Analysis on Possible Role of Combination of rhACE2, Angiotensin (1-7) and Angiotensin (1-9) as Effective Therapeutic Measure”. SN Comprehensive Clinical Medicine 22 (2020): 1-6.
  26. Fratta Pasini AM., et al. “Potential Role of Antioxidant and Anti-Inflammatory Therapies to Prevent Severe SARS-Cov-2 Complications”. Antioxidants 2 (2021): 272.
  27. Bernard I., et al. “Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19”. Viruses1 (2020): 29.
  28. Pellegrini D., et al. “Microthrombi as a Major Cause of Cardiac Injury in COVID-19: A Pathologic Study”. Circulation10 (2021): 1031-1042.
  29. Zhang S., et al. “SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19”. Journal of Hematology and Oncology 1 (2020): 120.
  30. Nuovo GJ., et al. “Endothelial cell damage is the central part of COVID-19 and a mouse model induced by injection of the S1 subunit of the spike protein”. Annals of Diagnostic Pathology 51 (2021): 151682.
  31. Petrone L., et al. “A whole blood test to measure SARS-CoV-2-specific response in COVID-19 patients”. Clinical Microbiology and Infection (2020).
  32. Hester CG and Frank MM. “Complement activation by IgG containing immune complexes regulates the interaction of C1q with its ligands”. Molecular Immunology 116 (2019): 117-130.
  33. Wang K., et al. “Elevated Angiotensin 1-7/Angiotensin II Ratio Predicts Favorable Outcomes in Patients With Heart Failure”. Circulation: Heart Failure7 (2020): e006939.
  34. Bellavite P., et al. “A colorimetric method for the measurement of platelet adhesion in microtiter plates”. Analytical Biochemistry 2 (1994): 444-450.
  35. Suzuki YJ and Gychka SG. “SARS-CoV-2 Spike Protein Elicits Cell Signaling in Human Host Cells: Implications for Possible Consequences of COVID-19 Vaccines”. Vaccines1 (2021).
  36. Causality assessment of an adverse event following immunization (AEFI): user manual for the revised WHO classification (Second edition). 2nd Edition edn. Geneva: World Health Organization (2018).
Citation: Paolo Bellavite. “Renin-Angiotensin System, SARS-CoV-2 and Hypotheses about Adverse Effects Following Vaccination”. EC Pharmacology and Toxicology 9.4 (2021): 01-10.

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