The ACE-2 in COVID-19: Foe or Friend?

Abstract

COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT₁R axis and ACE-2-Ang-(1–7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT₁R axis with a downregulation of ACE-2-Ang-(1–7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1–7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1–7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.

Key words

COVID-19 - ACE-2 - renin angiotensin system

• References

• 1 Special Expert Group for Control of the Epidemic of Novel Coronavirus Pneumonia of the Chinese Preventive Medicine Association [An update on the epidemiological characteristics of novel coronavirus pneumonia COVID-19]. Zhonghua Liu Xing Bing Xue Za Zhi 2020; 41: 139-144
• 2 Korean Society of Infectious Diseases, Korean Society of Pediatric Infectious Diseases, Korean Society of Epidemiology, Korean Society for Antimicrobial Therapy, Korean Society for Healthcare-associated Infection Control and Prevention, Korea Centers for Disease Control and Prevention. Report on the Epidemiological Features of Coronavirus Disease 2019 (COVID-19) Outbreak in the Republic of Korea from January 19 to March 2, 2020. J Korean Med Sci 2020; 35: e112
• 3 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 [Epub ahead of print]
• 4 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506
• 5 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 [Epub ahead of print]
• 6 Guan WJ, Ni ZY, Hu Y. et al. For the China Medical Treatment Expert Group for COVID-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 [Epub ahead of print]
• 7 Wu C, Chen X, Cai Y. et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern M. Ed. 2020 [Epub ahead of print]
• 8 Bornstein SR, Dalan R, Hopkins D. et al. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrinol. 2020
• 9 Yan R, Zhang Y, Li Y. et al. Structural basis for the recognition of the SARS-Cov-2 by full length human ACE-2. Science. 2020 [Epub ahead of print]
• 10 Zhang H, Penninger JM, Li Y. et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 [Epub ahead of print]
• 11 Donoghue M, Hsieh F, Baronas E. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000; 87: E1-E9
• 12 Hamming I, Timens W, Bulthuis ML. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203: 631-637
• 13 Lukassen S, Chua RL, Trefzer T. et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are predominantly expressed in a transient secretory cell type in subsegmental bronchial branches (preprint); bioRxiv. 2020
• 14 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020
• 15 Jia HP, Look DC, Shi L. et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol 2005; 79: 14614-14621
• 16 Kuba KY, Imai S, Rao H. et al. A crucial role of angiotensin converting enzyme 2(ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11: 875-879
• 17 Lambert DW, Hooper NM. Turner. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. AJ Biochem Pharmacol 2008; 75: 781-786
• 18 Ribeiro-Oliveira A, Nogueira AI, Pereira RM. et al. The renin-angiotensin system and diabetes: An update. Vasc Health Risk Manag 2008; 4: 787-803
• 19 Tikellis C, Thomas MC. Angiotensin-converting enzyme (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept. 2012 256294. 256294
• 20 Simões e Silva AC, Silveira KD, Ferreira AJ. et al. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol 2013; 169: 477-492
• 21 Song J, Hu B, Qu H. et al. Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells. Biochem Biophys Res Commun. 2020
• 22 Peters J. Peptides. Local renin-angiotensin systems in the adrenal gland. Peptides 2012; 34: 427-432
• 23 Nakayama T, Izumi Y, Soma M. et al. Adrenal renin-angiotensin-aldosterone system in streptozotocin-diabetic rats. Horm Metab Res 1998; 30: 12-15
• 24 Sadik NA, Metwally NS, Shaker OG. et al. Local renin-angiotensin system regulates the differentiation of mesenchymal stem cells into insulin -producing cells through angiotensin type 2 receptor. Biochimie 2017; 137: 132-138
• 25 Henricksen EJ, Prasannarong M. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle. Mol Cell Endocrinol 2013; 378: 15-22
• 26 Kawabe Y, Mori J, Morimoto H. et al. ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue. Am J Physiol Endocrinol Metab. 2019 317. E1140-E1149
• 27 Yang JK, Lin SS, Ji XJ. et al. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010; 47: 193-199
• 28 Hosseiny M, Kooraki S. Ali Gholamrezanezhad et al. Radiology perspective of coronavirus disease 2019 (COVID-19): Lessons from severe acute respiratory syndrome and middle east respiratory syndrome. Am J Roentgenol. 2020: 1-5 https://www.ajronline.org/doi/full/10.2214/AJR.20.22969
• 29 Tian S, Hu W, Niu L. et al. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) Pneumonia in two patients with Lung Cancer. J Thor Surg. 2020 [Epub ahead of print]
• 30 Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition) http://kjfy.meetingchina.org/msite/news/show/cn/3337.html; Accessed 21st March 2020
• 31 Xu Z, Shi L, Wang Y. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Me. d. 2020 [Epub ahead of print]
• 32 Thevarajan I, Nguyen THO, Koutsakos M. et al. Breadth of concomitant immune responses prior to patient recovery: A case report of non-severe COVID-19. Nat Med. 2020
• 33 Dong C, Xiaokuni L, Qifa S. Hypokalemia and clinical implications in patients with coronavirus disease 2019 (COVID-19).
• 34 Chen J, Jiang Q, Xia X. et al. Individual variation of the SARS-CoV2 receptor ACE2 gene expression and regulation. Preprints. 2020: 2020030191
• 35 Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020
• 36 Imai Y, Kuba K, Rao S. et al. ACE-2 protects from severe acute lung failure. Nature 2005; 436: 112-116
• 37 Zhang R, Pan Y, Fanelli V. et al. Mechanical stress and the induction of lung fibrosis via the midkine signalling pathway. Am J Respir Crit Care Med 2015; 192: 315-323
• 38 Wosten-van Asperen RM, Lutter R, Specht PA. et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE-2 activities and is prevented by Ang-(1-7) or an Ang II receptor antagonists. J Pathol 2011; 225: 618-627
• 39 Khan A, Benthim C, Zeno B. et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 2017; 21: 234
• 40 Deshotels MR, Xia H, Sriramula S. et al. Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II receptor type 1 receptor-dependent mechanism. Hypertension 2014; 64: 1368-1375
• 41 Sun ML, Yang JM, Sun YP. et al. [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43: E014 doi:10.3760/cma.j.issn.1001-0939.2020.0014
• 42 Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Published and accessed on: March 17. 2020
• 43 http://www.startribune.com/university-of-minnesota-to-test-three-drugs-for-covid-patients/568766632/ Accessed 21st March 2020