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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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“Downregulation of ACE2 is associated with both SARS-CoV and SARS-CoV-2 disease severity (21, 120, 121); this contrasts with a minimally symptomatic coronavirus strain, HCoV-NL63, that utilizes but does not cleave or downmodulate the ACE2 receptor (122).”
COVID-19: from an acute to chronic disease? Potential long-term health consequences
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Fotuhi, M., Mian, A., Meysami, S., & Raji, C. A. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200581 · Cited by 401
“ACE2 deficiency lessens the impact of SARS-Cov2 infection [32].”
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“tensin (1–7), recombinant ACE2 and angiotensin II blockers can be novel candidates in Covid‐19 infected patients.(11,52) Host protease (TMPRSS2 and furin) inhibitors can also exert a high potential for the treatment of SARS‐CoV‐2 infections.”
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“Therefore, blocking the interaction between spike protein and ACE-2 receptor is among the most promising options to treat the COVID-19 disease (Verdecchia et al., 2020).”
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Efforts at COVID-19 Vaccine Development: Challenges and Successes
Haque, A., & Pant, A. B. (2020) · Vaccines · doi:10.3390/vaccines8040739 · Cited by 141
“Several coronaviruses like SARS-CoV, NL63, and SARS-CoV-2 use ACE2 as the host receptor [9].”
BackgroundKrishnamachary, B., Cook, C. M., Kumar, A., Spikes, L. A., Chalise, P., & Dhillon, N. K. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12117 · Cited by 140
Design of multi-epitope vaccine candidate against SARS-CoV-2: ain-silicostudy
Peele, K. A., Srihansa, T., Krupanidhi, S., Ayyagari, V. S., & Venkateswarulu, T. C. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1770127 · Cited by 134
“The SARS-CoV-2 has a surface spike like glycoprotein (S-Spike), it binds specifically to angiotensinconverting enzyme 2 (ACE2) to access host type-2 pneumocyte cells that could bind to human cells (Hoffmann et al., 2020; Verdecchia et al., 2020).”
BackgroundElectrocardiographic features of patients with COVID-19 pneumonia
Angeli, F., Spanevello, A., Ponti, R. D., Visca, D., Marazzato, J., Palmiotto, G., Feci, D., Reboldi, G., Fabbri, L. M., & Verdecchia, P. (2020) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2020.06.015 · Cited by 134
Epigenetic mechanisms regulating COVID-19 infection
Chlamydas, S., Papavassiliou, A. G., & Piperi, C. (2020) · Epigenetics · doi:10.1080/15592294.2020.1796896 · Cited by 135
“SARS-CoV-2 is using the receptor-binding domain (RBD) of the spike (S1) protein that contains a core structure and a receptor-binding motif (RBM) to bind the outer surface of the receptor and enter the host [19].”
BackgroundSevere COVID-19 and aging: are monocytes the key?
Pence, B. D. (2020) · GeroScience · doi:10.1007/s11357-020-00213-0 · Cited by 137
“A recent comprehensive review (Verdeccia et al. 2020) makes a compelling argument that this loss of ACE2 is a proximate cause of lung inflammatory cell infiltration and ARDS and that conditions in which ACE2 is already reduced (including aging) may exacerbate the severity of COVID-19.”
BackgroundNanomedicine for COVID-19: the role of nanotechnology in the treatment and diagnosis of COVID-19
Vahedifard, F., & Chakravarthy, K. V. (2021) · Emergent Materials · doi:10.1007/s42247-021-00168-8 · Cited by 129
Annasamy, G., Kumar, N. A., & Anand, S. (2021) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2021.116205 · Cited by 131
Farshbafnadi, M., Zonouzi, S. K., Sabahi, M., Dolatshahi, M., & Aarabi, M. H. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111507 · Cited by 134
“These effects may be lethal in patients with underlying low levels of ACE2, e.g., in patients with heart failure (Verdecchia et al., 2020).”
Molecular pathways involved in COVID-19 and potential pathway-based therapeutic targets
Farahani, M., Niknam, Z., Amirabad, L. M., Dashatan, N. A., Koushki, M., Nemati, M., Pouya, F. D., Rezaei–Tavirani, M., Rasmi, Y., & Tayebi, L. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112420 · Cited by 126
“infection, due to the attachment of S protein to the ACE2 and internalization together with ACE2, leads to the depletion of membranal ACE2 and contributes to an increase in Ang II level and to the stimulation of AT1R [21].”
InfluentialEndothelial Dysfunction in Covid-19 Infection
Otifi, H. M., & Adiga, B. K. M. (2022) · The American Journal of the Medical Sciences · doi:10.1016/j.amjms.2021.12.010 · Cited by 129
“As there is already baseline ACE2R deficiency in the elderly (to a greater extent in men) and in patients with diabetes, hypertension, cardiac hypertrophy and heart failure, SARS-CoV-2 infection is likely to manifest more severely.(15)”
InfluentialSARS-CoV-2 vaccines: Lights and shadows
Angeli, F., Spanevello, A., Reboldi, G., Visca, D., & Verdecchia, P. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.04.019 · Cited by 125
“The loss of ACE2 receptor activity from the external site of the cellular membrane, as mediated by the interaction between ACE2 and SARS-CoV-2 Spike proteins, leads to less angiotensin II inactivation and less generation of antiotensin1–7 [44, 45].”
Carcaterra, M., & Caruso, C. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110412 · Cited by 122
“ACE2 is actually reduced as already suggested by some authors [31,40] and plays a possible protective role, also explaining why angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) [32,41], may also be protective.”
SARS-CoV-2 leads to a small vessel endotheliitis in the heart
Macciò, U., Zinkernagel, A. S., Shambat, S. M., Zeng, X., Cathomas, G., Ruschitzka, F. T., Schuepbach, R. A., Moch, H., & Varga, Z. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2020.103182 · Cited by 118
Male Fertility and the COVID-19 Pandemic: Systematic Review of the Literature
Khalili, M. A., Leisegang, K., Majzoub, A. A., Finelli, R., Selvam, M. K. P., Henkel, R., Moshrefi, M., & Agarwal, A. K. (2020) · The World Journal of Men s Health · doi:10.5534/wjmh.200134 · Cited by 117
“These receptors are widely expressed in the lungs (particularly type II pneumocytes and macrophages), cardiovascular system, gastrointestinal system, kidneys, neurological tissues, and the testes [10,17,18].”
BackgroundPlasma ACE2 predicts outcome of COVID-19 in hospitalized patients
Kragstrup, T. W., Singh, H. S., Grundberg, I., Nielsen, A. L., Rivellese, F., Mehta, A., Goldberg, M. B., Filbin, M. R., Qvist, P., & Bibby, B. M. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252799 · Cited by 117
“Moreover, Ang II has been found to activate several cells within the immune system, such as macrophages, leading to a higher production of proinflammatory cytokines like IL-6 and TNFα [35, 36, 38].”
BackgroundImpact of Diabetes in Patients Diagnosed With COVID-19
Abu‐Farha, M., Al‐Mulla, F., Thanaraj, T. A., Kavalakatt, S., Ali, H., Ghani, M. A., & Abubaker, J. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.576818 · Cited by 122
Marchianò, S., Hsiang, T.-Y., Khanna, A., Higashi, T., Whitmore, L. S., Bargehr, J., Davaapil, H., Chang, J., Smith, E. A., Ong, L. P., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.02.008 · Cited by 112
“This protein is expressed in different tissues of the human body, including cardiomyocytes and cardiac pericytes, and its primary function is to counterbalance the renin-angiotensin-aldosterone system (Chen et al., 2020a; Hikmet et al., 2020; Li et al., 2020; Verdecchia et al., 2020).”
Genetic Association of ACE2 rs2285666 Polymorphism With COVID-19 Spatial Distribution in India
Srivastava, A., Bandopadhyay, A., Das, D., Pandey, R. K., Singh, V., Khanam, N., Srivastava, N., Singh, P. P., Dubey, P. K., Pathak, A., et al. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.564741 · Cited by 111
Neutrophils in COVID-19: Not Innocent Bystanders
McKenna, E., Wubben, R., Isaza-Correa, J. M., Melo, A. M., Mhaonaigh, A. U., Conlon, N. P., O’Donnell, J. S., Cheallaigh, C. N., Hurley, T., Stevenson, N. J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.864387 · Cited by 117
“Following viral entry, the additional ACE2 deficiency may exacerbate the dysregulation between ACE!Angiotensin II!AT1 receptor axis (potentially adverse) and the ACE2!Angiotensin!Mas receptor axis (negative regulator of angiotensin II activity, potentially protective recombinant ACE2) (68).”
BackgroundInfluentialCurrent Strategies of Antiviral Drug Discovery for COVID-19
Mei, M., & Tan, X. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.671263 · Cited by 111
Antioxidant, anti-inflammatory and immunomodulatory roles of vitamins in COVID-19 therapy
Pisoschi, A. M., Pop, A., Iordache, F., Stanca, L., Geicu, O. I., Bîlteanu, L., & Șerban, A. I. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114175 · Cited by 118
“During this step, the above-described mechanism of intervention of vitamin D is highly important, as downregulation of angiotensin-converting enzyme 2 in the viral context is detrimental, primarily in subjects with baseline ACE2 impairment linked to old age, diabetes, hypertension or cardiovascular disease [194].”
Rheumatic manifestations of COVID-19: a systematic review and meta-analysis
Ciaffi, J., Melicòni, R., Ruscitti, P., Berardicurti, O., Giacomelli, R., & Ursini, F. (2020) · BMC Rheumatology · doi:10.1186/s41927-020-00165-0 · Cited by 106
“The finding of signs and symptoms of COVID-19 extending beyond the respiratory tract can be explained, at least in part, by the ubiquitous expression and tissue distribution of angiotensin-converting enzyme 2 (ACE2), the major SARS-CoV-2 entry receptor [5].”
BackgroundThe pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach
Morris, G., Bortolasci, C. C., Puri, B. K., OLIVE, L. S., Marx, W., O'Neil, A. E., Athan, E., Carvalho, A. F., Maes, M. H. J., Walder, K. R., et al. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118166 · Cited by 107
“In addition, the SARS-CoV-2 spike protein contains a Furin cleavage site in the spike protein that does not exist in SARS-CoV [22–24], allowing cleavage by cellular polyprotein convertases, such as furin and capthesin and potentially enhancing the efficiency of entry by endocytosis [12,25].”
BackgroundResultInfluentialSteinman, J. B., Lum, F., Ho, P. P.-K., Kaminski, N., & Steinman, L. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012358117 · Cited by 102
Pei, R., Feng, J., Zhang, Y., Sun, H., Li, L., Yang, X., He, J., Xiao, S., Xiong, J., Lin, Y., et al. (2020) · Protein & Cell · doi:10.1007/s13238-020-00811-w · Cited by 107
Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study
Ambrosino, P., Calcaterra, I. L., Molino, A., Moretta, P., Lupoli, R., Spedicato, G. A., Papa, A., Motta, A., Maniscalco, M., & Minno, M. N. D. D. (2021) · Biomedicines · doi:10.3390/biomedicines9080957 · Cited by 103
“Beyond this direct effect on endothelial function, angiotensin II also stimulates inflammation by activating NF-κB, thus enhancing the transcription of inflammatory cytokines and adhesion molecules and collagen deposition [70,76].”
BackgroundBiomarkers of post-covid depression
Lorkiewicz, P., & Waszkiewicz, N. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10184142 · Cited by 102
ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives
Saponaro, F., Rutigliano, G., Sestito, S., Bandini, L., Storti, B., Bizzarri, R., & Zucchi, R. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.588618 · Cited by 106
Alam, M. S., & Czajkowsky, D. M. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.11.001 · Cited by 111
“Although there is presently an incomplete understanding of the mechanisms underlying SARS-CoV-2 infection-induced oxidative stress, it is known that during infection, the availability of “free” ACE2 decreases owing to its binding to the virus and/or entry into the cells with the virus [82,83] (Fig.”
Bloise, E., Zhang, J., Nakpu, J., Hamada, H., Dunk, C., Li, S., Império, G. E., Nadeem, L., Kibschull, M., Lye, P., et al. (2020) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2020.08.055 · Cited by 101
Obesity and its impact on COVID-19
de Leeuw, A. J. M., Luttikhuis, M. A. M. O., Wellen, A. C., Müller, C., & Calkhoven, C. F. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02072-4 · Cited by 115
“, older age, hypertension, diabetes, cardiovascular disease, seem to develop a more severe disease [39].”
BackgroundFarsalinos, K. E., Eliopoulos, E., Leonidas, D. D., Papadopoulos, G. E., Tzartos, S. J., & Poulas, K. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165807 · Cited by 99
“This has been the focus of the global research community, examining the interactions between disease conditions or medications and ACE2 expression [4,5].”
BackgroundHoel, H., Heggelund, L., Reikvam, D. H., Stiksrud, B., Ueland, T., Michelsen, A. E., Otterdal, K., Muller, K. E., Lind, A., Müller, F., et al. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13178 · Cited by 97
Vascular Manifestations of COVID-19 – Thromboembolism and Microvascular Dysfunction
Roberts, K. A., Colley, L. S., Agbaedeng, T. A., Ellison, G. M., & Ross, M. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.598400 · Cited by 96
“This pathophysiological increase in Ang II and without the modulator and protective effects of Ang 1-7, results in downstream elevation of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells, further accelerating vascular inflammation and the facilitation of the coagulation cascade (42), thus resulting in…”
BackgroundACE/ACE2 Ratio: A Key Also in 2019 Coronavirus Disease (Covid-19)?
Pagliaro, P., & Penna, C. R. R. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00335 · Cited by 99
“Membrane-bound ACE2 has greater anti-inflammatory effects (47).”
Kruglikov, I. L., Shah, M., & Scherer, P. E. (2020) · eLife · doi:10.7554/elife.61330 · Cited by 98
COVID‐19 and seizures: Is there a link?
Vohora, D., Jain, S., Tripathi, M., & Potschka, H. (2020) · Epilepsia · doi:10.1111/epi.16656 · Cited by 94
The role of oxidative stress in the pathogenesis of infections with coronaviruses
Gain, C., Song, S., Angtuaco, T., Satta, S., & Kelesidis, T. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1111930 · Cited by 104
“Several redox mechanisms can regulate both viral entry and cytosolic replication of coronaviruses (Figure 2; Table 1; Wang and Zhang, 1999; Kulisz et al., 2002; Halestrap et al., 2004; Mizutani et al., 2004; Emerling et al., 2005; Kefaloyianni et al., 2006; Doughan et al., 2008; Lucas et al., 2008; Cho et al., 2009; G…”
BackgroundFigueiró-Filho, E. A., Yudin, M. H., & Farine, D. (2020) · Journal of Perinatal Medicine · doi:10.1515/jpm-2020-0364 · Cited by 93
Endothelial Cells in Emerging Viral Infections
Fosse, J. H., Haraldsen, G., Falk, K., & Edelmann, R. J. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.619690 · Cited by 99
“This makes it tempting to speculate if some of the positive effects of glucocorticoidtreatment in severe COVID-19 (197) could be mediated by vascular stabilisation.”
BackgroundInfluentialAngiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases
El-Arif, G., Khazaal, S., Farhat, A., Harb, J., Annweiler, C., Wu, Y., Cao, Z., Kovacic, H., Khattar, Z. A., Fajloun, Z., et al. (2022) · Molecules · doi:10.3390/molecules27072048 · Cited by 99
“Once in the cytoplasm, the viral genome codes for the synthesis of proteins necessary for the replication and spread of SARS-CoV-2 [9].”
BackgroundInfluentialOverview of COVID-19 inflammatory pathogenesis from the therapeutic perspective
Lee, C.-H., & Choi, W. J. (2021) · Archives of Pharmacal Research · doi:10.1007/s12272-020-01301-7 · Cited by 93
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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