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A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm.
Elife. 2020 Jul 07; 9E

Abstract

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.

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Authors+Show Affiliations

Garvin MR
Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, United States.
Alvarez C
Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, United States.
Miller JI
Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, United States.
Prates ET
Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, United States.
Walker AM
Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, United States. University of Tennessee Knoxville, The Bredesen Center for Interdisciplinary Research and Graduate Education, Knoxville, United States.
Amos BK
University of Kentucky, Department of Horticulture, Lexington, United States.
Mast AE
Versiti Blood Research Institute, Medical College of Wisconsin, Milwaukee, United States.
Justice A
VA Connecticut Healthcare/General Internal Medicine, Yale University School of Medicine, West Haven, United States.
Aronow B
University of Cincinnati, Cincinnati, United States. Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, United States.
Jacobson D
Oak Ridge National Laboratory, Biosciences Division, Oak Ridge, United States. University of Tennessee Knoxville, The Bredesen Center for Interdisciplinary Research and Graduate Education, Knoxville, United States. University of Tennessee Knoxville, Department of Psychology, Austin Peay Building, Knoxville, United States.

MeSH

Angiotensin-Converting Enzyme 2AngiotensinsBetacoronavirusBradykininBronchoalveolar Lavage FluidCOVID-19Coronavirus InfectionsFemaleHumansMalePandemicsPeptidyl-Dipeptidase APneumonia, ViralReninRenin-Angiotensin SystemSARS-CoV-2TranscriptomeVasodilation

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

32633718

Clinical Trial Links

Baseline Vitamin D Deficiency and COVID-19 Disease Severity

Citation

Garvin, Michael R., et al. "A Mechanistic Model and Therapeutic Interventions for COVID-19 Involving a RAS-mediated Bradykinin Storm." ELife, vol. 9, 2020.
Garvin MR, Alvarez C, Miller JI, et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. Elife. 2020;9.
Garvin, M. R., Alvarez, C., Miller, J. I., Prates, E. T., Walker, A. M., Amos, B. K., Mast, A. E., Justice, A., Aronow, B., & Jacobson, D. (2020). A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. ELife, 9. https://doi.org/10.7554/eLife.59177
Garvin MR, et al. A Mechanistic Model and Therapeutic Interventions for COVID-19 Involving a RAS-mediated Bradykinin Storm. Elife. 2020 Jul 7;9 PubMed PMID: 32633718.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. AU - Garvin,Michael R, AU - Alvarez,Christiane, AU - Miller,J Izaak, AU - Prates,Erica T, AU - Walker,Angelica M, AU - Amos,B Kirtley, AU - Mast,Alan E, AU - Justice,Amy, AU - Aronow,Bruce, AU - Jacobson,Daniel, Y1 - 2020/07/07/ PY - 2020/5/21/received PY - 2020/7/6/accepted PY - 2020/7/8/pubmed PY - 2020/8/22/medline PY - 2020/7/8/entrez KW - COVID-19 KW - bradykinin KW - computational biology KW - human KW - human biology KW - hyaluronic acid KW - medicine KW - pathogenesis KW - renin-angiotensin system KW - systems biology JF - eLife JO - Elife VL - 9 N2 - Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/32633718/A_mechanistic_model_and_therapeutic_interventions_for_COVID_19_involving_a_RAS_mediated_bradykinin_storm_ DB - PRIME DP - Unbound Medicine ER -