Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection

A growing body of clinical evidence shows that vascular leakage leads to pulmonary edema in coronavirus disease 2019 (COVID-19) patients. Coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) use membrane ectopeptidases to invade cells, most notably dipeptidyl peptidase 4 (DPP4; https://www.uniprot.org/uniprot/P27487), aminopeptidase N (APN; https://www.uniprot.org/uniprot/P15144), and angiotensin-converting enzyme 2 (ACE2; https://www.uniprot.org/uniprot/Q9BYF1).[1] It is important to distinguish this latter protein from ACE, which is the main target for conventional blood pressure lowering drugs: ACE inhibitors do not inhibit ACE2.[2] As a result of virus entry, these membrane ectopeptidases are internalized and their activity becomes downregulated. The common denominator between these membrane ectopeptidases is their enzyme specificity: they degrade peptide hormones, for instance, angiotensin II. For SARS-CoV-2 (as well as SARS-CoV), ACE2 is the predominant target for cellular uptake in vivo.[3] It is present on lung alveolar epithelial cells, enterocytes of the small intestine, endothelial cells, and arterial smooth muscle cells.[4] In an acid aspiration lung injury mouse model, ACE2 knockout (KO) worsened the resulting edema.[5] This was accompanied by increased angiotensin II levels[6] and was prevented by angiotensin II receptor KO, leading to the conclusion that the lack of ACE2-mediated angiotensin II degradation was responsible for the observed increase pulmonary vascular permeability. The same observations were made when downregulating ACE2 with the spike protein of the SARS CoV prior to acid aspiration.[6] Yet, the authors did not measure renin in these studies. This is crucial since normally angiotensin II rises result in rapid renin suppression,[7] thereby normalizing its levels. Moreover, ACE2 is just one of many angiotensin-degrading enzymes (angiotensinases). In full accordance with this concept, Gurley et al did not find increased angiotensin II levels after ACE2 KO.[8] Hence, whether the ACE2 KO dependent permeability changes are entirely due to ACE2-mediated angiotensin II degradation remains uncertain. ACE2 has multiple other substrates. Among these are the kinins, which are also degraded by DPP4.[9] We and others believe that this deserves attention, as it offers an alternative view, and forms a basis on which novel therapeutic opportunities might be proposed.[10]

Publication History

Article published online:
11 June 2020

• References

• 1 Bosch BJ, Smits SL, Haagmans BL. Membrane ectopeptidases targeted by human coronaviruses. Curr Opin Virol 2014; 6: 55-60
• 2 Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275 (43) 33238-33243
• 3 Zhou P, Yang XL, Wang XG. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579 (7798): 270-273
• 4 Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203 (02) 631-637
• 5 Imai Y, Kuba K, Rao S. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436 (7047): 112-116
• 6 Kuba K, Imai Y, Rao S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11 (08) 875-879
• 7 Arendse LB, Danser AHJ, Poglitsch M. et al. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev 2019; 71 (04) 539-570
• 8 Gurley SB, Allred A, Le TH. et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 2006; 116 (08) 2218-2225
• 9 Vickers C, Hales P, Kaushik V. et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002; 277 (17) 14838-14843
• 10 van de Veerdonk FL, Netea MG, van Deuren M. et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. eLife 2020; 9: 9
• 11 De Maat S, Hofman ZLM, Maas C. Hereditary angioedema: the plasma contact system out of control. J Thromb Haemost 2018; 16 (09) 1674-1685
• 12 Levesque L, Larrivée JF, Bachvarov DR, Rioux F, Drapeau G, Marceau F. Regulation of kinin-induced contraction and DNA synthesis by inflammatory cytokines in the smooth muscle of the rabbit aorta. Br J Pharmacol 1995; 116 (01) 1673-1679
• 13 Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol 2020; 20 (05) 269-270
• 14 Saameli K, Eskes TK. Bradykinin and cardiovascular system: estimation of half-life. Am J Physiol 1962; 203: 261-265
• 15 Cyr M, Lepage Y, Blais Jr C. et al. Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma. Am J Physiol Heart Circ Physiol 2001; 281 (01) H275-H283
• 16 Byrd JB, Touzin K, Sile S. et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension 2008; 51 (01) 141-147
• 17 Mahmoudpour SH, Baranova EV, Souverein PC, Asselbergs FW, de Boer A, Maitland-van der Zee AH. PREDICTION-ADR consortium. Determinants of angiotensin-converting enzyme inhibitor (ACEI) intolerance and angioedema in the UK Clinical Practice Research Datalink. Br J Clin Pharmacol 2016; 82 (06) 1647-1659
• 18 Hurford R, Rezvani S, Kreimei M. et al. Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke. J Neurol Neurosurg Psychiatry 2015; 86 (05) 520-523
• 19 Pahs L, Droege C, Kneale H, Pancioli A. A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator administration. Ann Emerg Med 2016; 68 (03) 345-348
• 20 Cheong E, Dodd L, Smith W, Kleinig T. Icatibant as a potential treatment of life-threatening alteplase-induced angioedema. J Stroke Cerebrovasc Dis 2018; 27 (02) e36-e37
• 21 Maas C. Plasminflammation-an emerging pathway to bradykinin production. Front Immunol 2019; 10: 2046
• 22 Sodhi CP, Wohlford-Lenane C, Yamaguchi Y. et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg⁹ bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol 2018; 314 (01) L17-L31
• 23 Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review. Eur Radiol 2020; (e-pub ahead of print) DOI: 10.1007/s00330-020-06801-0.
• 24 van de Veerdonk FN, Netea MG, van Deuren M. et al. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints 2020; (e-pub ahead of print) DOI: 10.20944/preprints202004.0023.v1.
• 25 Cicardi M, Banerji A, Bracho F. et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010; 363 (06) 532-541
• 26 Banerji A, Busse P, Shennak M. et al. Inhibiting plasma kallikrein for hereditary angioedema prophylaxis. N Engl J Med 2017; 376 (08) 717-728
• 27 Ramchand J, Patel SK, Srivastava PM, Farouque O, Burrell LM. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLoS One 2018; 13 (06) e0198144