CC BY 4.0 · TH Open 2020; 04(02): e138-e144
DOI: 10.1055/s-0040-1713678
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Pathological Role of Angiotensin II in Severe COVID-19

Wolfgang Miesbach
1   Department of Haemostaseology and Haemophilia Center, Institute of Transfusion Medicine, Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany
› Author Affiliations
Further Information

Publication History

16 April 2020

19 May 2020

Publication Date:
26 June 2020 (online)

Abstract

The activated renin–angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin–angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1–7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin–angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1–7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.

 
  • References

  • 1 Chan JF, Yuan S, Kok KH. , et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020; 395 (10223): 514-523
  • 2 de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016; 14 (08) 523-534
  • 3 Drosten C, Günther S, Preiser W. , et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348 (20) 1967-1976
  • 4 Zhong NS, Zheng BJ, Li YM. , et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003. Lancet 2003; 362 (9393): 1353-1358
  • 5 Chen N, Zhou M, Dong X. , et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
  • 6 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
  • 7 Guan WJ, Ni ZY, Hu Y. , et al. China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020
  • 8 Stebbing J, Phelan A, Griffin I. , et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis 2020; 20 (04) 400-402
  • 9 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13) 1239-1242
  • 10 Zhou F, Yu T, Du R. , et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
  • 11 Zhang J, Dong X, Cao Y. , et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy; 2020
  • 12 Huang C, Wang Y, Li X. , et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
  • 13 Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39 (05) 529-539
  • 14 Kim ES, Choe PG, Park WB. , et al. Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med Sci 2016; 31 (11) 1717-1725
  • 15 Xu Z, Shi L, Wang Y. , et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8 (04) 420-422
  • 16 Dunham-Snary KJ, Wu D, Sykes EA. , et al. Hypoxic pulmonary vasoconstriction: from molecular mechanisms to medicine. Chest 2017; 151 (01) 181-192
  • 17 Grein J, Ohmagari N, Shin D. , et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; DOI: 10.1056/NEJMoa2007016.
  • 18 Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence 2014; 5 (01) 4-11
  • 19 Ryan D, Frohlich S, McLoughlin P. Pulmonary vascular dysfunction in ARDS. Ann Intensive Care 2014; 4: 28
  • 20 Burnham EL, Janssen WJ, Riches DWH, Moss M, Downey GP. The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance. Eur Respir J 2014; 43 (01) 276-285
  • 21 Yang X, Yu Y, Xu J. , et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 8 (05) 475-481
  • 22 Wang D, Hu B, Hu C. , et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 201585: 1-9
  • 23 Qi D YX, Tang X eal. Epidemiological and clinical features of 2019-nCoV acute respiratory disease cases in Chongqing municipality, China: a retrospective, descriptive, multiple-center study. Medrxiv 2019
  • 24 Zhong J, Basu R, Guo D. , et al. Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation 2010; 122 (07) 717-728 , 18, 728
  • 25 Kassiri Z, Zhong J, Guo D. , et al. Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail 2009; 2 (05) 446-455
  • 26 Lippi G. Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis 2020
  • 27 Shi S, Qin M, Shen B. , et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA; 2020
  • 28 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
  • 29 Klok FA. , et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020
  • 30 Fox SE. , et al. Pulmonary and cardiac pathology in COVID-19: the first autopsy series from New Orleans. Chemrxiv Pre-Print 2020. [Epub Ahead of Print]
  • 31 Skeggs Jr LT, Kahn JR, Lentz K, Shumway NP. The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J Exp Med 1957; 106 (03) 439-453
  • 32 Nehme A, Zouein FA, Zayeri ZD, Zibara K. An update on the tissue renin angiotensin system and its role in physiology and pathology. J Cardiovasc Dev Dis 2019; 6 (02) 14
  • 33 Paz Ocaranza M, Riquelme JA, García L. , et al. Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 2020; 17 (02) 116-129
  • 34 Crackower MA, Sarao R, Oudit GY. , et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002; 417 (6891): 822-828
  • 35 Hamming I, Timens W, Bulthuis MLC, 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
  • 36 Forrester SJ, Booz GW, Sigmund CD. , et al. Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev 2018; 98 (03) 1627-1738
  • 37 Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020; 46 (04) 586-590
  • 38 Ou X, Liu Y, Lei X. , et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11 (01) 1620
  • 39 Kuba K, Imai Y, Rao S, Jiang C, Penninger JM. Lessons from SARS: control of acute lung failure by the SARS receptor ACE2. J Mol Med (Berl) 2006; 84 (10) 814-820
  • 40 Huang F, Guo J, Zou Z. , et al. Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients. Nat Commun 2014; 5: 3595
  • 41 Imai Y, Kuba K, Rao S. , et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436 (7047): 112-116
  • 42 Zou Z, Yan Y, Shu Y. , et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun 2014; 5: 3594
  • 43 Packer M, McMurray JJV. Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure. Lancet 2017; 389 (10081): 1831-1840
  • 44 Khanna A, English SW, Wang XS. , et al; ATHOS-3 Investigators. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017; 377 (05) 419-430
  • 45 Farina N, Bixby A, Alaniz C. Angiotensin II brings more questions than answers. P&T 2018; 43 (11) 685-687
  • 46 Powell JS, Clozel JP, Müller RK. , et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989; 245 (4914): 186-188
  • 47 Prescott MF, Webb RL, Reidy MA. Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol 1991; 139 (06) 1291-1296
  • 48 Marshall RP, Gohlke P, Chambers RC. , et al. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol 2004; 286 (01) L156-L164
  • 49 Celi A, Cianchetti S, Dell'Omo G, Pedrinelli R. Angiotensin II, tissue factor and the thrombotic paradox of hypertension. Expert Rev Cardiovasc Ther 2010; 8 (12) 1723-1729
  • 50 Puurunen MK, Hwang SJ, Larson MG. , et al. ADP platelet hyperreactivity predicts cardiovascular disease in the FHS (Framingham Heart Study). J Am Heart Assoc 2018; 7 (05) e008522
  • 51 Markiewicz M, Richard E, Marks N, Ludwicka-Bradley A. Impact of endothelial microparticles on coagulation, inflammation, and angiogenesis in age-related vascular diseases. J Aging Res 2013; 2013: 734509
  • 52 Kamińska M, Mogielnicki A, Stankiewicz A. , et al. Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats. J Physiol Pharmacol 2005; 56 (04) 571-585
  • 53 Senchenkova EY, Russell J, Yildirim A, Granger DN, Gavins FNE. Novel role of T Cells and IL-6 (interleukin-6) in angiotensin II-induced microvascular dysfunction. Hypertension 2019; 73 (04) 829-838
  • 54 Skurk T, Lee YM, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 2001; 37 (05) 1336-1340
  • 55 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993; 87 (06) 1969-1973
  • 56 Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA. ; HEART Study Investigators. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997; 96 (02) 442-447
  • 57 Wu Y, Wang T, Guo C. , et al. Plasminogen improves lung lesions and hypoxemia in patients with COVID-19. QJM 2020; hcaa121
  • 58 Ekholm M, Kahan T, Jörneskog G, Bröijersen A, Wallén NH. Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo. Thromb Res 2009; 124 (01) 110-115
  • 59 Han Y, Runge MS, Brasier AR. Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors. Circ Res 1999; 84 (06) 695-703
  • 60 Funakoshi Y, Ichiki T, Ito K, Takeshita A. Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells. Hypertension 1999; 34 (01) 118-125
  • 61 Oudit GY, Kassiri Z, Jiang C. , et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009; 39 (07) 618-625
  • 62 Liu Y, Yang Y, Zhang C. , et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020; 63 (03) 364-374
  • 63 Ferrario CM. ACE2: more of Ang-(1-7) or less Ang II?. Curr Opin Nephrol Hypertens 2011; 20 (01) 1-6
  • 64 Gallagher PE, Ferrario CM, Tallant EA. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 2008; 295 (06) H2373-H2379
  • 65 Ocaranza MP, Godoy I, Jalil JE. , et al. Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 2006; 48 (04) 572-578
  • 66 Skowasch D, Viktor A, Schneider-Schmitt M, Lüderitz B, Nickenig G, Bauriedel G. Differential antiplatelet effects of angiotensin converting enzyme inhibitors: comparison of ex vivo platelet aggregation in cardiovascular patients with ramipril, captopril and enalapril. Clin Res Cardiol 2006; 95 (04) 212-216
  • 67 Montón M, Jiménez A, Núñez A. , et al. Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation. J Cardiovasc Pharmacol 2000; 35 (06) 906-913
  • 68 Monteil V, Kwon H, Prado P. , et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020; 181 (04) 905-913.e7
  • 69 Burger D, Montezano AC, Nishigaki N, He Y, Carter A, Touyz RM. Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts. Arterioscler Thromb Vasc Biol 2011; 31 (08) 1898-1907