RAS and bradykinin pathways in COVID-19 (WP4969)
Homo sapiens
This pathway describes imbalances in RAS and Bradykinin pathways in COVID-19. The expression of several genes in these pathways is affected in by SARS-CoV-2: * SERPING1 is downregulated, which cancels the suppression of F12 of the intrinsic coagulation cascade, resulting in the production of bradykinin from kallikrein and KNG. * ACE is downregulated, which increases bradykinin levels. * ACE2 is upregulated, ACE is downregulated, which causes an increase in Angiotensin 1-9 and sensitization of bradykinin receptors. * NFkappaB is suppressed by SARS-Cov-2, decreasing its binding to the ACE promoter and subsequent transcription. The result of a hyperactive bradykinin system is vasodilation to the point of vascular leakage and infiltration of inflammatory cells. The pathway is based on figure 2A from [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410499/ Garvin et al.]
Authors
Kristina Hanspers , Egon Willighagen , Friederike Ehrhart , Marvin Martens , Penny Nymark , Eric Weitz , and Denise SlenterActivity
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Organisms
Homo sapiensCommunities
COVID-19Annotations
Pathway Ontology
disease pathwayDisease Ontology
COVID-19Cell Type Ontology
vascular associated smooth muscle cell| Label | Type | Compact URI | Comment |
|---|---|---|---|
| 20-HETE | Metabolite | chebi:34306 | |
| Vitamin D3 | Metabolite | chebi:28940 | |
| bradykinin, des-arg(9) | Metabolite | chebi:133068 | |
| L-arginine | Metabolite | chebi:16467 | |
| Aldosterone | Metabolite | cas:52-39-1 | |
| Bradykinin | Metabolite | hmdb:HMDB0004246 | |
| Angiotensin II | Metabolite | hmdb:HMDB0001035 | |
| Angiotensin I | Metabolite | pubchem.compound:3081372 | |
| Ang 1-7 | Metabolite | chemspider:110354 | |
| Ang 1-9 | Metabolite | kegg.compound:C15851 | |
| Arachidonic acid | Metabolite | chebi:15843 | |
| Ca++ | Metabolite | hmdb:HMDB0000464 | |
| Guanosine triphosphate | Metabolite | chebi:15996 | |
| nitric oxide | Metabolite | chebi:16480 | |
| Cyclic guanosine monophosphate | Metabolite | chebi:16356 | |
| nitric oxide | Metabolite | chebi:16480 | |
| L-arginine | Metabolite | chebi:16467 | |
| Prostaglandin E2 | Metabolite | cas:363-24-6 | |
| Prostaglandin I2 | Metabolite | cas:35121-78-9 | |
| Prostaglandin E2 | Metabolite | cas:363-24-6 | |
| Prostaglandin I2 | Metabolite | cas:35121-78-9 | |
| SERPINE1 | GeneProduct | ncbigene:5054 | SERPINE1 codes for plasminogen activator inhibitor-1 (PAI-1) |
| NFKB1 | GeneProduct | ensembl:ENSG00000109320 | |
| VDR | GeneProduct | ensembl:ENSG00000111424 | |
| MAPK1 | GeneProduct | ensembl:ENSG00000100030 | |
| SERPING1 | GeneProduct | ensembl:ENSG00000149131 | |
| CYP24A1 | GeneProduct | ensembl:ENSG00000019186 | |
| KLK1 | GeneProduct | ensembl:ENSG00000167748 | |
| F12 | GeneProduct | ensembl:ENSG00000131187 | |
| KLKB1 | GeneProduct | ensembl:ENSG00000164344 | |
| AGTR1 | GeneProduct | ncbigene:185 | |
| CPN1 | GeneProduct | ensembl:ENSG00000120054 | |
| AGTR2 | GeneProduct | ncbigene:186 | |
| BDKRB1 | GeneProduct | ncbigene:623 | |
| KNG1 | GeneProduct | ncbigene:3827 | |
| ACE | GeneProduct | ncbigene:1636 | |
| REN | GeneProduct | ncbigene:5972 | |
| ACE2 | GeneProduct | ncbigene:59272 | |
| AGT | GeneProduct | ncbigene:183 | |
| ACE | GeneProduct | ncbigene:1636 | |
| BDKRB2 | GeneProduct | ncbigene:624 | |
| CYP3A4 | GeneProduct | ensembl:ENSG00000160868 | |
| CYP3A4 | GeneProduct | ensembl:ENSG00000160868 | |
| ACE | GeneProduct | ncbigene:1636 | |
| PRKG1 | GeneProduct | ensembl:ENSG00000185532 | |
| RHOA | GeneProduct | ensembl:ENSG00000067560 | |
| ROCK1 | GeneProduct | ensembl:ENSG00000067900 | |
| NOS1 | GeneProduct | ensembl:ENSG00000089250 | |
| NOS3 | GeneProduct | ensembl:ENSG00000164867 | |
| ACE2 | GeneProduct | ensembl:ENSG00000130234 | |
| TNF | GeneProduct | ensembl:ENSG00000232810 | |
| IL1A | GeneProduct | hgnc.symbol:IL1A | |
| NFKB1 | GeneProduct | hgnc.symbol:NFKB1 | |
| IL1B | GeneProduct | hgnc.symbol:IL1B | |
| IL1A | GeneProduct | hgnc.symbol:IL1A | |
| IL1B | GeneProduct | hgnc.symbol:IL1B | |
| IL1A | GeneProduct | hgnc.symbol:IL1A | |
| IL1B | GeneProduct | hgnc.symbol:IL1B | |
| Guanylate cyclase | Protein | uniprot:A0A140VJE6 |
References
- The control of protein phosphatase-1 by targetting subunits. The major myosin phosphatase in avian smooth muscle is a novel form of protein phosphatase-1. Alessi D, MacDougall LK, Sola MM, Ikebe M, Cohen P. Eur J Biochem. 1992 Dec 15;210(3):1023–35. PubMed Europe PMC Scholia
- Characterization of the receptor and the mechanisms underlying the inflammatory response induced by des-Arg9-BK in mouse pleurisy. Vianna RM, Calixto JB. Br J Pharmacol. 1998 Jan;123(2):281–91. PubMed Europe PMC Scholia
- Guanylate cyclase and the .NO/cGMP signaling pathway. Denninger JW, Marletta MA. Biochim Biophys Acta. 1999 May 5;1411(2–3):334–50. PubMed Europe PMC Scholia
- Pharmacogenetics of antihypertensive drug responses. Schwartz GL, Turner ST. Am J Pharmacogenomics. 2004;4(3):151–60. PubMed Europe PMC Scholia
- Effects of renin-angiotensin system inhibition on end-organ protection: can we do better? Weir MR. Clin Ther. 2007 Sep;29(9):1803–24. PubMed Europe PMC Scholia
- Role of bradykinin, nitric oxide, and angiotensin II type 2 receptor in imidapril-induced angiogenesis. Li P, Kondo T, Numaguchi Y, Kobayashi K, Aoki M, Inoue N, et al. Hypertension. 2008 Feb;51(2):252–8. PubMed Europe PMC Scholia
- Are we poised to target ACE2 for the next generation of antihypertensives? Ferreira AJ, Raizada MK. J Mol Med (Berl). 2008 Jun;86(6):685–90. PubMed Europe PMC Scholia
- Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection. de Maat S, de Mast Q, Danser AHJ, van de Veerdonk FL, Maas C. Semin Thromb Hemost. 2020 Oct;46(7):835–7. PubMed Europe PMC Scholia
- COVID-19 and pneumonia: a role for the uPA/uPAR system. D’Alonzo D, De Fenza M, Pavone V. Drug Discov Today. 2020 Aug;25(8):1528–34. PubMed Europe PMC Scholia
- A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, et al. Elife. 2020 Jul 7;9:e59177. PubMed Europe PMC Scholia
- The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection. Carvalho PR de, Sirois P, Fernandes PD. Peptides. 2021 Jan;135:170428. PubMed Europe PMC Scholia
- Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Bernard I, Limonta D, Mahal LK, Hobman TC. Viruses. 2020 Dec 26;13(1):29. PubMed Europe PMC Scholia