The DOI matches its Crossref record; 84 of the 85 references it cites were found in a registry or an index.
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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1 retracted
Li, Y., Cao, Y., Zeng, Z., Liang, M., Xue, Y., Xi, C., Zhou, M. S., & Jiang, W. (2015) · Scientific Reports · doi:10.1038/srep08209 · Cited by 104 · cited 1×
“[29, [31] [32] [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.”
BackgroundRetractedHoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286 · cited 4×
“The present review discusses the role of angiotensin converting enzyme 2 (ACE2) receptors which are not only the door through which the virus enters into cells, [2,3] but also the conductor of several pathophysiological reactions associated with the clinical features of the disease, with potential therapeutic implicat…”
InfluentialCOVID-19: consider cytokine storm syndromes and immunosuppression
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., & Manson, J. J. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30628-0 · Cited by 9,664 · cited 1×
“[69,70] In this context, administration of soluble recombinant ACE2 [12] or angiotensin1-7 [71] could be promising therapeutic approaches, requiring urgent evaluation in clinical trials.”
Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
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“The present review discusses the role of angiotensin converting enzyme 2 (ACE2) receptors which are not only the door through which the virus enters into cells, [2,3] but also the conductor of several pathophysiological reactions associated with the clinical features of the disease, with potential therapeutic implicat…”
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Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus
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“[20] Anti-ACE2 antibodies, but not anti-ACE antibodies are able to block SARS-Cov viral invasion, [7] which is also blocked by N-(2-aminoethil)-1 aziridine-ethamine, a specific ACE-2 inhibitor.”
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“[59] A meta-analysis of 8 studies conducted in China on a total of 46,248 patients infected with SARS-CoV2 confirmed that hypertension, diabetes and history of cardiovascular disease were the most frequent comorbidities in these patients.”
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“[51] Pneumocytes type 2 are responsible for the production of alveolar surfactant, and in the same time they function as ‘stem’ cells, progenitors of pneumocytes type I (95% of all pneumocytes) which are responsible of gas exchanges.”
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“[54] Patients with hypertension were older that those without hypertension (66 vs 62 years, p=0.”
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“[56] Again, hypertension and history of cardiovascular disease were significantly more prevalent among the more severe patients.”
BackgroundInfluential
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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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