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The pivotal link between ACE2 deficiency and SARS-CoV-2 infection
Open accessAbstract
Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin 1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin 1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the 'adverse' ACE→Angiotensin II→AT1 receptor axis and the 'protective' ACE2→Angiotensin 1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin 1-7. In this setting, recombinant ACE2, angiotensin 1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.
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“Of note, SARS-CoV and SARS-CoV-2 cell entry results in downregulation of ACE2 (Verdecchia et al., 2020)”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Verdecchia et al., 2020
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InfluentialSoluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?
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SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19?
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“[28,42] ACE2 receptors are also expressed in the adipose tissue [43,44] and a reduction of ACE2 has been noted in the adipose tissue of obese animals [44] In animal experiments, diets rich of fats decreased ACE2 activity and angiotensin1-7, and increased angiotensin II and blood pressure levels in male, but not in fem…”
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InfluentialOrgan-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents
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Structure-Based Discovery of a Novel Angiotensin-Converting Enzyme 2 Inhibitor
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The Antithrombotic Effect of Angiotensin-(1-7) Involves Mas-Mediated NO Release from Platelets
Fraga-Silva, R. A., Pinheiro, S. V. B., Gonçalves, A. C. D. C., Alenina, N. V., Bäder, M., & Santos, R. A. S. (2008) · Molecular Medicine · doi:10.2119/2007-00073.fraga-silva · Cited by 146 · cited 3×
“[35,36] Animals knockout for Mas receptors have a shorter bleeding time and increased size of thrombi.”
Patel, S. K., Velkoska, E., Freeman, M., Wai, B., Lancefield, T. F., & Burrell, L. M. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00227 · Cited by 138 · cited 1×
“[14,64] Treatment with soluble recombinant ACE2 reduces the blood pressure rise provoked by angiotensin II, increases angiotensin1-7 and reduces angiotensin II.”
Antithrombotic Effect of Captopril and Losartan Is Mediated by Angiotensin-(1-7)
Kucharewicz, I., Pawlak, R., Matys, T., Pawlak, D., & Buczko, W. (2002) · Hypertension · doi:10.1161/01.hyp.0000035396.27909.40 · Cited by 131 · cited 1×
“The ACE2→Angiotensin1-7→Mas receptor axis exerts anti-thrombotic effects [35-38].”
Jessup, J. A., Gallagher, P. E., Averill, D. B., Brosnihan, K. B., Tallant, E. A., Chappell, M. C., & Ferrario, C. M. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00061.2006 · Cited by 128
Recinos, A., LeJeune, W. S., Sun, H., Lee, C. Y., Tieu, B. C., Lu, M., Hou, T., Boldogh, I. R., Tilton, R. G., & Brasier, A. R. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.10.013 · Cited by 120 · cited 2×
“[22,48-50] Tracheal instillation of cigarette smoke, [49] or particulate matter of aerodynamic diameter of less than 2,5 ɥm, [50] induces acute lung injury with release of inflammatory cytokines IL-6, TNF-α and TGF-β1 and increased expression of ACE, consistent with ACE→Angiotensin II→AT1 receptor axis over-activity.”
Yamamoto, S., Yancey, P. G., Zuo, Y., Ma, L.-J., Kaseda, R., Fogo, A. B., Ichikawa, I., Linton, M. F., Fazio, S., & Kon, V. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.237198 · Cited by 115 · cited 1×
“[26,27] It is important to remark that the deleterious effects of angiotensin II summarized above almost entirely result from the stimulation of AT1 receptors.”
An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect
Fraga-Silva, R. A., Costa-Fraga, F. P., Sousa, F. B. D., Alenina, N. V., Bäder, M., Sinisterra, R. D., & Santos, R. A. S. (2011) · Clinics · doi:10.1590/s1807-59322011000500021 · Cited by 107 · cited 2×
“[39] Stimulation of Mas receptors by angiotensin1-7 increases prostacyclin and NO release.”
Patel, V. B., Basu, R., & Oudit, G. Y. (2016) · Adipocyte · doi:10.1080/21623945.2015.1131881 · Cited by 104 · cited 1×
“[46] Obese patients with heart failure have an increased amount of epicardial adipose tissue [46] and it has been suggested that ACE2 deficiency can induce heart failure with preserved ejection fraction in animals.”
ACE2 at the centre of COVID-19 from paucisymptomatic infections to severe pneumonia
Rivellese, F., & Prediletto, E. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102536 · Cited by 103 · cited 1×
“[53] 6. Clinical characteristics of patients infected with SARS-CoV and SARS-CoV-2”
Classic and Nonclassic Renin-Angiotensin Systems in the Critically Ill
Bitker, L., & Burrell, L. M. (2019) · Critical Care Clinics · doi:10.1016/j.ccc.2018.11.002 · Cited by 102 · cited 1×
“[18, 19] 4. ACE2: angels or devils?”
MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides
Gallagher, P. E., Ferrario, C. M., & Tallant, E. A. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00145.2008 · Cited by 100 · cited 1×
“The possibility that ACE inhibitors and angiotensin II receptor blockers (ARBs) may be discontinued even temporarily, because these drugs appear to increase the expression of ACE2 receptors, the site of viral entry into the human organism, [72-75] is actively debated.”
Magalhães, G. S., Rodrigues‐Machado, M. D. G., Motta‐Santos, D., Silva, A. R., Caliari, M. V., Prata, L. O., Abreu, S. C., Rocco, P. R. M., Barcelos, L. S., Santos, R. A. S., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13057 · Cited by 97 · cited 2×
“[29,31-33] ACE2 is expressed on the luminal side of the bronchial ciliated epithelia, where it removes a single amino acid residue also from the polypeptide des-Arg [9] bradykinin (DABK), [6] thereby preventing the binding of DABK on the bradykinin receptor B1 receptor.”
Liang, B., Wang, X., Zhang, N., Yang, H., Bai, R., Liu, M., Bian, Y., Xiao, C., & Yang, Z. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000374047 · Cited by 86
Fang, C., Stavrou, E. X., Schmaier, A. A., Grobe, N., Morris, M., Chen, A., Nieman, M. T., Adams, G. N., Larusch, G. A., Zhou, Y., et al. (2013) · Blood · doi:10.1182/blood-2012-09-459156 · Cited by 84 · cited 3×
“[35, 36] Animals knockout for Mas receptors have a shorter bleeding time and increased size of thrombi.”
BackgroundInfluentialHung, Y.-H., Hsieh, W., Hsieh, J. S., Liu, F.-C., Tsai, C.-H., Lu, L.-C., Huang, C.-Y., Wu, C.-L., & Lin, C. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.13379 · Cited by 81 · cited 1×
“[22,48-50] Tracheal instillation of cigarette smoke, [49] or particulate matter of aerodynamic diameter of less than 2,5 ɥm, [50] induces acute lung injury with release of inflammatory cytokines IL-6, TNF-α and TGF-β1 and increased expression of ACE, consistent with ACE→Angiotensin”
Angiotensin-(1-7) attenuates lung fibrosis by way of Mas receptor in acute lung injury
Chen, Q., Yang, Y., Huang, Y., Pan, C. S., Liu, L., & Qiu, H. (2013) · Journal of Surgical Research · doi:10.1016/j.jss.2013.06.052 · Cited by 67 · cited 1×
“[29,31-33] ACE2 is expressed on the luminal side of the bronchial ciliated epithelia, where it removes a single amino acid residue also from the polypeptide des-Arg [9] bradykinin (DABK), [6] thereby preventing the binding of DABK on the bradykinin receptor B1 receptor.”
Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARS-CoV-2 Infection?
Peiró, C., & Moncada, S. (2020) · Circulation · doi:10.1161/circulationaha.120.047297 · Cited by 66
Trask, A. J., Averill, D. B., Ganten, D., Chappell, M. C., & Ferrario, C. M. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01198.2006 · Cited by 58 · cited 1×
“[23] To understand the relevance of angiotensin II degradation by ACE2 results, it is important to review the biological effects of angiotensin II.”
Yamagata, R., Nemoto, W., Nakagawasai, O., Takahashi, K., & Tan–No, K. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113825 · Cited by 44 · cited 1×
“[61-63] Several experimental and clinical studies indicate that ACE2 deficiency obtained through deletion or inhibition may be a causative factor for hypertension.”
Pai, W., Lo, W., Hsu, T., Peng, C., & Wang, H.-J. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00994 · Cited by 41 · cited 1×
“The ACE2→Angiotensin1-7→Mas receptor axis exerts anti-thrombotic effects [35-38].”
Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease
Wang, W., Patel, V. B., Parajuli, N., Dong, F., Basu, R., Wang, Z., Ramprasath, T., Kassiri, Z., Penninger, J. M., & Oudit, G. Y. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1149-y · Cited by 40 · cited 1×
“[68] Given the above premises, it is tempting to speculate (Figure 2) that ACE2 deficiency may play a central role in the pathogenesis of SARSCoV-2 infection.”
Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease
Wysocki, J. A., Goodling, A., Burgaya, M., Whitlock, K. B., RUZINSKI, J. T., BATLLE, D. C., & Afkarian, M. (2017) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00074.2017 · Cited by 39
ACE-inibitori, sartani e sindrome respiratoria acuta da coronavirus 2
Verdecchia, P., Reboldi, G., Cavallini, C., Mazzotta, G., & Angeli, F. (2020) · Giornale italiano di cardiologia · doi:10.1714/3343.33127 · Cited by 35
Li, Y., Li, Y., Li, G., Song, Y., & Gong, X. (2013) · PubMed · doi:10.3275/8951 · Cited by 32
Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and coronavirus
Verdecchia, P., Angeli, F., & Reboldi, G. (2020) · Journal of Hypertension · doi:10.1097/hjh.0000000000002469 · Cited by 29 · cited 1×
“[80,83] It is hoped that the results of the above mentioned NCT04312009 and NCT04311177 trials will answer this question.”
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1 of the 85 references couldn’t be matched to a known paper.
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CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells
Wang, K., Chen, W., Zhang, Z., Deng, Y., Lian, J., Du, P. F., Wei, D., Yang, Z., Sun, X., Gong, L., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00426-x · Cited by 1,630
Chua, R. L., Lukassen, S., Trump, S., Hennig, B. P., Wendisch, D., Pott, F., Debnath, O., Thürmann, L., Kurth, F., Völker, M. T., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0602-4 · Cited by 1,035
How COVID-19 induces cytokine storm with high mortality
Hojyo, S., Uchida, M., Tanaka, K., Hasebe, R., Tanaka, Y., Murakami, M., & Hirano, T. (2020) · Inflammation and Regeneration · doi:10.1186/s41232-020-00146-3 · Cited by 663
COVID-19 infection: an overview on cytokine storm and related interventions
Montazersaheb, S., Khatibi, S. M. H., Hejazi, M. S., Tarhriz, V., Farjami, A., Sorbeni, F. G., Farahzadi, R., & Ghasemnejad, T. (2022) · Virology Journal · doi:10.1186/s12985-022-01814-1 · Cited by 657
“In the case of ACE2 receptors, it is hypothesized that the COVID-19 first attacks several organs expressing ACE2 receptors, such as the heart, brain, vessels, liver, kidney, and, more importantly, lung [25].”
BackgroundImmunity, endothelial injury and complement-induced coagulopathy in COVID-19
Perico, L., Benigni, A., Casiraghi, F., Ng, L. F. P., Rénia, L., & Remuzzi, G. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-00357-4 · Cited by 616
Metadata
- Authors
- Verdecchia, P., Cavallini, C., Spanevello, A., & Angeli, F.
- Affiliations
- University of Insubria (IT)
- Corresponding author
- Verdecchia, Paolo
- Venue
- European Journal of Internal Medicine
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 76
- Pages
- 14-20
- ISSN
- 0953-6205 (ISSN-L)
- PMC
- PMC7167588
- OpenAlex
- W3017331996
- Cited by
- 1,237
- References
- 85
- Citations by year
- 2026: 22 · 2025: 50 · 2024: 84 · 2023: 156 · 2022: 245 · 2021: 384 · 2020: 295
- FWCI
- 45.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Internal Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- ACE2 receptor, COVID-19 pandemic, angiotensin II, angiotensin-(1-7), Mas receptor, angiotensin II type 1 receptor, lung inflammation, thrombosis, hypertension, diabetes mellitus, cardiovascular disease, angiotensin receptor blockers, COVID-19 severity
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Angiotensins, Diabetes Mellitus, Heart Failure, Humans, Hypertension, Peptidyl-Dipeptidase A, Pneumonia, Viral, Receptors, Virus, Recombinant Proteins, Risk Factors, Coronavirus Infections, Angiotensin II Type 1 Receptor Blockers, Drug Discovery, Pandemics
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