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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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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
Walls, A. C., Park, Y.-J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020) · doi:10.1101/2020.02.19.956581 · Cited by 8,586 · 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…”
InfluentialWu, C., Chen, X., Cai, Y., Xia, J., Zhou, X., Xu, S., Huang, H., Zhang, L., Zhou, X., Du, C., et al. (2020) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2020.0994 · Cited by 8,249
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus
Li, W., Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., Somasundaran, M., Sullivan, J. L., Luzuriaga, K., Greenough, T. C., et al. (2003) · Nature · doi:10.1038/nature02145 · Cited by 5,923 · cited 3×
“[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.”
Tang, N., Li, D., Wang, X., & Sun, Z. (2020) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14768 · Cited by 5,770 · cited 1×
“[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.”
Hamming, I., Timens, W., Bulthuis, M., Lely, A., Navis, G., & van Goor, H. (2004) · The Journal of Pathology · doi:10.1002/path.1570 · Cited by 5,676 · cited 1×
“[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.”
Grasselli, G., Zangrillo, A., Zanella, A., Antonelli, M., Cabrini, L., Castelli, A., Cereda, D., Coluccello, A., Foti, G., Fumagalli, R., et al. (2020) · JAMA · doi:10.1001/jama.2020.5394 · Cited by 5,469 · cited 3×
“[54] Patients with hypertension were older that those without hypertension (66 vs 62 years, p=0.”
Yang, J., Zheng, Y., Gou, X., Pu, K., Chen, Z., Guo, Q., Ji, R., Wang, H., Wang, Y., & Zhou, Y. (2020) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2020.03.017 · Cited by 4,206 · cited 4×
“[56] Again, hypertension and history of cardiovascular disease were significantly more prevalent among the more severe patients.”
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Bhardwaj, V., Cruz, M. D., Subramanyam, D., Kumar, R. C., Markan, S., Parker, B., & Roy, H. K. (2022) · PLoS ONE · doi:10.1371/journal.pone.0271303 · Cited by 10
“For example, levels of ACE2 have also been shown to correlate with the risk of SARS-CoV-2 infection [13].”
BackgroundCOVID-19 inhibits spermatogenesis in the testes by inducing cellular senescence
Wang, Z., Ma, Y., Chen, Z., Yang, R., Liu, Q., Pan, J., Wang, J., Liu, Y., Zhou, M., Zhang, Y., et al. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.981471 · Cited by 10
“COVID-19 invades the human body through ACE2 receptor and harms not only the respiratory system, but also various organswith highACE2 expression, according to clinical data frommultiple sites (Verdecchia et al., 2020;Walls et al., 2020).”
BackgroundPitfalls of Thrombotic Microangiopathies in Children: Two Case Reports and Literature Review
Mocanu, A., Bogos, R. A., Lazaruc, T. I., Cianga, A. L., Lupu, V. V., Ioniuc, I. K., Alecsa, M., Lupu, A., Ivanov, A. V., Miron, I. C., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13071228 · Cited by 11
“This leads to the release of pro-inflammatory chemo-attractants such as C3a and C5a, which recruit more leukocytes [47].”
BackgroundRothlin, R. P., Pelorosso, F. G., Duarte, M., Nicolosi, L., Criado, I. F., Salgado, M. V., & Vetulli, H. M. (2023) · Pharmacology Research & Perspectives · doi:10.1002/prp2.1083 · Cited by 10
Ahmadi, S., & Khaledi, S. (2023) · Analytical Cellular Pathology · doi:10.1155/2023/8883492 · Cited by 12
“Understanding the possible mechanisms of neuroinvasion by the virus can help to identify better treatment strategies and prevent its damaging effects on the CNS and PNS [87].”
InfluentialBlood ACE2 Protein Level Correlates with COVID-19 Severity
Shevchuk, O. O., Pak, A., Palii, S. M., Ivankiv, Y. I., Kozak, K., Korda, M. M., & Vari, S. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813957 · Cited by 10
“Genetic ACE2 deficiency is one more aspect that can exacerbate the COVID-19 lung injury [32,33].”
BackgroundRepurposing current therapeutic regimens against SARS-CoV-2 (Review)
Konstantinidou, S. M., & Papanastasiou, I. P. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8905 · Cited by 10
“The therapeutic approaches (51) against ACE2‐mediated COVID‐19 may involve: i) Vaccine production based on the spike S protein (52), ii) inhibition of virus and host cell fusion via transmembrane protease serine 2 (TMPRSS2) (53,54) and iii) blocking ACE2 receptor (55,56).”
BackgroundJehpsson, L., Sun, J., Nilsson, P. M., Edsfeldt, A., & Swärd, P. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.622179 · Cited by 10
“ANGII interacts with the angiotensin II type 1 receptor subtype (AT1R), which leads to vasoconstriction and activation of pro-inflammatory and pro-fibrotic pathways (Skurk et al., 2004; Oudit and Pfeffer, 2020; Wang et al., 2020).”
BackgroundMethodInfluentialCOVID-19 associated thromboinflammation of renal capillary: potential mechanisms and treatment.
Chen, X., Yu, C., Jing, H., Wang, C., Zhao, X., Zhang, J., Zhang, S., Liu, H., Xie, R., & Shi, J. (2020) · Europe PMC (PubMed Central) · Cited by 10
Wang, L., Ren, Z., Ma, L., Han, Y., Wei, W., Jiang, E., & Ji, X.-Y. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.592888 · Cited by 10
“In addition, ACE2 is widely attached to the extracellular surfaces of the lungs, arteries, heart, kidneys, intestines, and brain (cell membranes) (16, 28, 29).”
BackgroundImpact of Cardiovascular Diseases on COVID-19: A Systematic Review
Cao, Q., Lei, H., Yang, M., Wei, L., Dong, Y., Xu, J., Nasser, M., Liu, M., Zhu, P., Xu, L., et al. (2021) · Medical Science Monitor · doi:10.12659/msm.930032 · Cited by 10
“Subsequently, the virions appear to cause a subsequent membrane fusion, resulting in entry into host cells, along with the membrane receptor [14].”
BackgroundShoily, S. S., Ahsan, T., Fatema, K., & Sajib, A. A. (2021) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2021.104888 · Cited by 10
Grinevich, V. B., Kravchuk, Y. A., Ped, V. I., Sas, E. I., Salikova, S. P., Владимировна, Г. И., Ei, T., Sitkin, S. I., Лазебник, Л. Б., Голованова, Е. В., et al. (2021) · Экспериментальная и клиническая гастроэнтерология · doi:10.31146/1682-8658-ecg-187-3-5-82 · Cited by 12
Malato, J., Sotzny, F., Bauer, S., Freitag, H., Fonseca, A., Grabowska, A. D., Graça, L., Cordeiro, C., Nacul, L., Lacerda, E., et al. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e07665 · Cited by 11
Treatment Options for COVID-19–Related Guillain-Barré Syndrome
Goudarzi, S., Esmaeeli, S., Valencia, J. D., Lu, M. E., Hales, R. R., Fehnel, C. R., Conley, C. M., Quraishi, S. A., & Nozari, A. (2021) · The Neurologist · doi:10.1097/nrl.0000000000000342 · Cited by 10
Mannino, F., Bitto, A., & Irrera, N. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.592169 · Cited by 9
“Therefore, lung damage and inflammation primarily start following the specifying binding to ACE2, but probably it is not the only viral mechanism (Behl et al., 2020; Bordallo et al., 2020; Verdecchia et al., 2020).”
BackgroundMayneris‐Perxachs, J., Moreno‐Navarrete, J. M., Ballanti, M., Monteleone, G., Paoluzi, O. A., Mingrone, G., Lefèbvre, P., Staels, B., Federici, M., Puig, J., et al. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.11.007 · Cited by 9
“However, while ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut and lung, ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form [9].”
SARS-CoV-2–host cell surface interactions and potential antiviral therapies
Butnariu, A.-B., Look, A., Grillo, M., Tabish, T. A., McGarvey, M. J., & Pranjol, M. Z. I. (2021) · Interface Focus · doi:10.1098/rsfs.2020.0081 · Cited by 9
“Unfortunately, the entry of SARS-CoV-2 into the cells through membrane fusion markedly downregulates ACE2 receptors; with loss of the catalytic effect of these receptors, side effects ensue, such as increased pulmonary inflammation and coagulation [23].”
BackgroundCOVID-19-associated myocarditis: clinical pattern and medical treatment
Sergeeva, V. A., & Te, L. (2022) · Russian Medical Inquiry · doi:10.32364/2587-6821-2022-6-1-26-32 · Cited by 9
Adverse Reactions to Anti-Infective Vaccines: an Emerging Problem in the COVID-19 Era
Escudero, C., Montaño, P. P., & Audicana, M. T. (2022) · Current Treatment Options in Allergy · doi:10.1007/s40521-022-00311-8 · Cited by 9
“The S1 subunit of the spike protein, detected in the bloodstream up to 2 weeks after vaccination [74], can trigger thrombosis and other adverse inflammatory reactions, including activation of the kallikrein-bradykinin system [75].”
BackgroundDemir, S. T., Dalgıç, N., Yeşiltaş, S. K., Özyürek, E. B. A., Karapapak, M., Uzun, S. Ü., & Güven, D. (2022) · Photodiagnosis and Photodynamic Therapy · doi:10.1016/j.pdpdt.2022.103157 · Cited by 9
“ACE-2 receptors are widely expressed in many parts of the body, including the heart, blood vessels (vascular endothelial and smooth cells), intestines, lungs, kidneys, testes, and brain [16].”
Gospodarczyk, A. Z., Wojciechowska, C., Marczewski, K. P., Gospodarczyk, N. J., & Zalejska–Fiolka, J. (2022) · Medicine · doi:10.1097/md.0000000000031540 · Cited by 9
“Under normal conditions, ACE2 is involved in the modulation of the renin-angiotensin-aldosterone system, which is responsible for the conversion of angiotensin II to angiotensin (1–7), resulting in vasodilatory, anti-inflammatory, antithrombotic, antiproliferative, antifibrotic, and antiarrhythmic effects.[34] ACE2 de…”
BackgroundZn2+ and Cu2+ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein
Pelucelli, A., Peana, M., Orzeł, B., Piasta, K., Gumienna‐Kontecka, E., Medici, S., & Zoroddu, M. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119202 · Cited by 9
“At the same time, a large number of zinc-deficient patients are more prone to developing severe COVID-19 [54,55].”
BackgroundInfluentialKhadela, A. D., Soni, S., Megha, K., Bhagat, S. U., & Chavda, V. P. (2023) · Biologics · doi:10.3390/biologics3020008 · Cited by 9
“The ACE2 receptor, responsible for the entry of SARS-CoV-2, is not only present in the lungs but also in the endothelium and heart, which leads to microvascular dysfunction in patients with severe disease [51].”
BackgroundSchnekenberg, L. G., Sedghi, A., Schoene, D., Pallesen, L., Barlinn, J., Woitek, F. J., Linke, A. H.-P., Puetz, V., Barlinn, K., Mangner, N., et al. (2023) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd10070297 · Cited by 11
“This interaction causes a substantial down-regulation of cellular ACE2, which is attached to cellular membranes in multiple organs including the heart [4,16].”
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“ACE2 has been identified as a receptor for SARS-CoV-2, the virus that causes COVID-19, allowing the virus to enter host cells [57].”
Backgroundde Sousa, R. B. N., Nascimento, L. D. D., Costa, L. H. A., Leite, V. R. M. C., Borges, C. L., de Deus, J. M., Rebelo, A., Pinheiro, D. D. S., & Pedrino, G. (2023) · PLoS ONE · doi:10.1371/journal.pone.0288178 · Cited by 7
Petitjean, S. J. L., Eeckhout, S., Delguste, M., Zhang, Q., Durlet, K., & Alsteens, D. (2023) · Nano Letters · doi:10.1021/acs.nanolett.3c03550 · Cited by 9
Serwaa, A., Oyawoye, F. O., Owusu, I. A., Dosoo, D., Manu, A. A., Sobo, A. K., Fosu, K., Olwal, C. O., Quashie, P. K., & Aikins, A. R. (2024) · Scientific Reports · doi:10.1038/s41598-024-75718-1 · Cited by 9
Household pets and SARS-CoV2 transmissibility in the light of the ACE2 intrinsic disorder status
Uversky, V. N., Elrashdy, F., Aljaddawi, A. A., & Redwan, E. M. M. M. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1821784 · Cited by 9
“The cellular receptors for spike SARS-Co-V2 viral entry suggested to be angiotensin converting enzyme (ACE2) protein which are expressed in the brain, gut, heart, kidney, lung (particularly in type 2 pneumocytes and macrophages), vessels, and testis (Verdecchia et al., 2020).”
BackgroundCOVID-19 and the heart: direct and indirect impact
Канорский, С. Г. (2021) · Кубанский научный медицинский вестник · doi:10.25207/1608-6228-2021-28-1-16-31 · Cited by 13
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Flinn, B. B., Royce, N., Gress, T., Chowdhury, N. C., & Santanam, N. (2021) · Obesity Reviews · doi:10.1111/obr.13225 · Cited by 8
Hmazzou, R., Marc, Y., Flahault, A., Gerbier, R., Mota, N. D., & Llorens‐Cortés, C. (2021) · Clinical Science · doi:10.1042/cs20201385 · Cited by 9
Illi, B., Vasapollo, B., Valensise, H. C. C., & Totta, P. (2021) · Reproductive Medicine · doi:10.3390/reprodmed2020010 · Cited by 9
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BackgroundSevere Type of COVID-19: Pathogenesis, Warning Indicators and Treatment
Shi, K., Liu, Y., Zhang, Q., Ran, C., Hou, J., Zhang, Y., & Wang, X. (2021) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-021-3313-x · Cited by 10
“Abnormal activation of ACE/Ang II axis leads to pulmonary vasoconstriction, inflammation, fibrosis, hypertrophy, and accumulation of reactive oxygen species.((12,58))”
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Gallo, A., Pero, E., Pellegrino, S., Macerola, N., Murace, C. A., Ibba, F., Agnitelli, M. C., Landi, F., & Montalto, M. (2022) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2022.04.002 · Cited by 9
“In these conditions, the consequent angiotensin II effects may result in exacerbation of hypertension, cardiac hypertrophy, and maladaptive left ventricular remodeling after a myocardial infarction.(75) Therefore, ACE2 deficiency seems to play a key role in the pathogenesis but also in the prognosis of COVID-19 infect…”
Santa, S. A., Doku, D., Olwal, C. O., Brown, C. A., Tagoe, E. A., & Quaye, O. (2022) · Future Microbiology · doi:10.2217/fmb-2021-0233 · Cited by 10
Matsoukas, J., Gadanec, L. K., Zulli, A., Apostolopoulos, V., Kelaidonis, K., Ligielli, I., Moschovou, K., Georgiou, N., Plotas, P., Chasapis, C. T., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10071731 · Cited by 9
“This function is a pivotal link between the ACE2 deficiency and SARS-CoV-2 infection [1,4,81,82].”
BackgroundInfluentialDobrynina, M. A., Zurochka, A. V., Komelkova, M. V., Luo, S., Александрович, З. В., Hu, D., Ryabova, L. V., & Sarapultsev, A. (2022) · Russian Journal of Immunology · doi:10.46235/1028-7221-1160-soc · Cited by 9
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Sadeghi, S., Mobarakeh, S. R., Momenzadeh, M., Aria, A., Heidarpour, M., Hajiahmadi, S., & Naderi, Z. (2023) · Clinical Case Reports · doi:10.1002/ccr3.7339 · Cited by 9
Davarpanah, M. A., Adatorwovor, R., Mansoori, Y., Ramsheh, F. S. R., Parsa, A., Hajiani, M., Faramarzi, H., Kavuluru, R., & Asadipooya, K. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02141-0 · Cited by 7
“We used the standard 5% significance level for testing our entire hypothesis with the rejection of the null hypothesis for p -values less than 0.05.”
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Angiotensin‐converting enzyme as a new immunologic target for the new SARS‐CoV‐2
Hallaj, S., Ghorbani, A., Mousavi‐Aghdas, S. A., Mirza‐Aghazadeh‐Attari, M., Севбитов, А. В., Hashemi, V., Hallaj, T., & Jadidi‐Niaragh, F. (2020) · Immunology and Cell Biology · doi:10.1111/imcb.12396 · Cited by 8
“Several studies reported that processes such as aging, HTN, atherosclerosis and heart failure could result in ACE II deficiency.(78) Interestingly, the aging-induced ACE II deficiency occurs considerably more frequently in men than in women.”
BackgroundHost genetic factors and susceptibility to SARS‐CoV ‐2 infection
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Nanoantidote for repression of acidosis pH promoting COVID‐19 infection
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Molecular Docking - Recent Advances
Istıflı, E. S. (2022) · Biomedical engineering · doi:10.5772/intechopen.100665 · Cited by 8
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“In other words, different mechanisms of Ang II cleavage and accumulation may be involved in a unique pathophysiological mechanism explaining the risk of the progression to severe forms of COVID-19 [8,12].”
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“ACE2 expression is downregulated by SARS-CoV infection, which may contribute to the impairment of dopamine production [41 – 43].”
BackgroundHoughton, M. J., Balland, É., Gartner, M. J., Thomas, B. J., Subbarao, K., & Williamson, G. (2024) · BioFactors · doi:10.1002/biof.2084 · Cited by 8
“It seems that SARS-CoV-2 entry into cells downregulates ACE2 65 and this contributes to COVID-19 pathophysiology via instigation of the hyperinflammatory cytokine storm and manifestation of cardiovascular disruption, 66 while maintenance of ACE2 levels could help to alleviate this.”
Insights into Potential Mechanisms of Injury and Treatment Targets in COVID-19, SARS-Cov-2 Infection
Zhyvotovska, A., Yusupov, D., Foronjy, R., Nakeshbandi, M., McFarlane, S. I., & Salifu, M. O. (2020) · International Journal of Clinical Research & Trials · doi:10.15344/2456-8007/2020/147 · Cited by 7
“Elevated levels of circulating soluble ACE2 are a sign of increased activity of the RAAS system and are associated with a worse prognosis [5].”
BackgroundInfluentialInfección por SARS-CoV-2 y ataque cerebrovascular isquémico
Marín‐Medina, D. S., Muñoz-Rosero, Á. M., Bernal-Bastidas, B. L., & Toro, J. M. G. (2020) · Medicina de Familia SEMERGEN · doi:10.1016/j.semerg.2020.09.007 · Cited by 24
Chaudhari, S., Pereira, S. D., Asare-Werehene, M., Naha, R., Kabekkodu, S. P., Tsang, B. K., & Satyamoorthy, K. (2021) · Journal of Ovarian Research · doi:10.1186/s13048-021-00787-z · Cited by 8
Adil, M. S., Verma, A., Rudraraju, M., Narayanan, S. P., & Somanath, P. R. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30343 · Cited by 8
“ACE2 is abundantly expressed in the heart, blood vessels, lung, bronchus, gut, kidney, testis, and brain (Verdecchia et al., 2020) and also reported being expressed in lung alveolar epithelial cells (Bourgonje et al., 2020).”
BackgroundDivisi, D., Zaccagna, G., Angeletti, C., Cicerone, E., Vico, A. D., Moretti, R., Imbriglio, G., Carbuglia, N., Quaglione, G. R., Ranieri, S. C., et al. (2021) · Clinical Case Reports · doi:10.1002/ccr3.4262 · Cited by 8
Hu, S., Hu, Z., Qin, J., Lin, C., & Jiang, X. (2021) · Aging · doi:10.18632/aging.203159 · Cited by 9
“ACE2 deficiency is shown to increase the severity of SARS-CoV-2 infection due to the inflammation inhibitory effect of ACE2 via degrading angiotensin II [15].”
BackgroundInfluentialPhysical activity and exercise as an essential medical strategy for the COVID-19 pandemic and beyond
Seman, S., Dražilov, S. S., Ilić, V., Tesic, M. B., Stojiljković, S., Arena, R. A., & Popović, D. (2021) · Experimental Biology and Medicine · doi:10.1177/15353702211028543 · Cited by 8
“Exercise, through changes in body composition, might affect the balance in regulation between the ACE/AngII/ AT1R and ACE2/Ang(1–7)/MasR regulatory axes.(12,72,73) Previous review states that the (Ang1–7)/MasR arm inhibits lipogenesis and stimulates lipolysis,(73) and we suggest that moderate-intensity continuous exer…”
BackgroundInfluentialFemale fertility under the impact of COVID-19 pandemic: a narrative review
Wang, M., Zhang, B., & Jin, L. (2021) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2021.19 · Cited by 8
Ting, C.-T., & Chen, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073649 · Cited by 8
“lished that angiotensin-converting enzyme 2 (ACE2) is the main receptor for SARS-CoV-2 cell entry [59], there is no stop to identifying novel receptors that may potentiate the SARS-CoV-2 infectivity.”
BackgroundLehtinen, M. J., Kumar, R., Zabel, B., Mäkelä, S. M., Nedveck, D. A., Tang, P., Latvala, S., Guery, S., & Budinoff, C. R. (2022) · iScience · doi:10.1016/j.isci.2022.104445 · Cited by 8
“As it has been shown that SARS-CoV-2 infection decreases ACE2 on the cell membrane (Verdecchia et al., 2020), the results suggest that OL-1 and OL-2 groups may have had lower duodenal viral infection and replication compared to placebo.”
Fan, Y., Wei, J., Wang, W., Li, C., Pan, G., Keiffer, T. R., Bao, J., & Zhou, Z. (2022) · Pathogens · doi:10.3390/pathogens11060672 · Cited by 8
Müller, W. E. G., Wang, X., Neufurth, M., & Schröder, H. C. (2022) · Progress in molecular and subcellular biology · doi:10.1007/978-3-031-01237-2_7 · Cited by 8
Is SARS-CoV-2 a Risk Factor of Bipolar Disorder?—A Narrative Review
Lorkiewicz, P., & Waszkiewicz, N. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11206060 · Cited by 8
Mariniello, D. F., Allocca, V., D’Agnano, V., Villaro, R., Lanata, L., Bagnasco, M., Aronne, L., Bianco, A., & Perrotta, F. (2022) · Molecules · doi:10.3390/molecules27248919 · Cited by 9
“On the other hand, the level of angiotensin 1-7 is diminished [21].”
BackgroundQiao, Y., Zhan, Y., Zhang, Y., Deng, J., Chen, A., Liu, B., Zhang, Y., Pan, T. S., Zhang, W., Zhang, H., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.992062 · Cited by 8
“HEK293T and HEK293T-hACE2 cell lines were cultured in Dulbecco’s modified Eagle medium (DMEM; Gibco) supplemented with 10% fetal bovine serum (FBS; Gibco) and 1% penicillinstreptomycin (Gibco) at 37°C with 5% CO2.”
BackgroundInfluentialSabzian‐Molaei, F., Hosseini, S., Alipour, A., Ghaderi, H., Fotouhi-Chahooki, F., Hadi, A., & Shahsavarani, H. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154648 · Cited by 8
“As a result, a drug that inhibits ACE2 acts like a double-edged sword; while it prevents the virus from entering the host cell, it causes inflammatory complications and can lead to the patient’s death during the treatment phase (Verdecchia et al., 2020).”
BackgroundInfluentialKeller, G. A., Colaianni, I., Coria, J., Girolamo, G. D., & Miranda, S. E. (2023) · Respiratory Medicine · doi:10.1016/j.rmed.2023.107155 · Cited by 8
“Additionally, sACE2 levels can cleave circulating AngII and, as a consequence, downregulates its pro-inflammatory actions [15,16].”
BackgroundCOVID-19, a viral endocrinological disease?
Grassi, T., Varotto, E., & Galassi, F. M. (2020) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2020.06.003 · Cited by 8
“While attention has been paid to the role of ACE2 inhibition by SARS-CoV-2 through a tight binding mechanism, either as an ancillary or only recently as an important aspect of this disease [3,4], our view is that this very inhibition is truly responsible for the cascade of events ultimately resulting in the described…”
Ischemic Stroke among the Symptoms Caused by the COVID-19 Infection
Szelenberger, R., Saluk, J., & Bijak, M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9092688 · Cited by 8
“SARS-CoV-2 binding with the ACE2 receptor leads to its down-regulation, increasing harmful and pathological state development in the host organism [50].”
BackgroundCzick, M. E., Shapter, C., & Shapter, R. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s265518 · Cited by 8
Determinants of circulating angiotensin-converting enzyme 2 protein levels in the general population
Kuznetsova, T., & Cauwenberghs, N. (2020) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2020.10.012 · Cited by 8
“However, we acknowledge that there is no compelling evidence of a connection between baseline level of circulating ACE2 and the susceptibility to and severity of SARS-CoV-2 infection [9].”
Peters, E. M. J., Schedlowski, M., Watzl, C., & Gimsa, U. (2021) · PPmP - Psychotherapie · Psychosomatik · Medizinische Psychologie · doi:10.1055/a-1322-3205 · Cited by 9
Assar, S., Pournazari, M., Soufivand, P., Mohamadzadeh, D., & Sanaee, S. (2021) · The Egyptian Rheumatologist · doi:10.1016/j.ejr.2021.03.001 · Cited by 8
Feng, F., Chen, J., Zhao, J., Li, Y., Li, M., & Sun, C. (2021) · Viruses · doi:10.3390/v13112243 · Cited by 8
“Especially, downregulation of ACE2 induced by viral invasion could be more detrimental in individuals with a variable degree of ACE2 deficiency; for example, elder age, diabetes, hypertension, and prior heart diseases including heart failure [49].”
BackgroundLi, M., Xiao, L., Cai, J., Jiang, K., Li, Y., Li, S., Wang, Q., Wang, W., Shi, K., & Liu, H. (2024) · Journal of Global Health · doi:10.7189/jogh.14.05001 · Cited by 7
“Here, SARS-CoV-2 can directly bind to ACE2 [33], leading to an imbalance in the conversion of angiotensin 2 to angiotensin 1.”
BackgroundAngiotensinergic effect of β-Caryophyllene on Lipopolysaccharide- induced systemic inflammation
Espinoza-Gutiérrez, H. A., López-Salido, S. C., Flores-Soto, M. E., Tejeda-Martínez, A. R., Chaparro-Huerta, V., & Paredes, J. M. V. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150081 · Cited by 7
Potential Effects of Hyperglycemia on SARS-CoV-2 Entry Mechanisms in Pancreatic Beta Cells
Michaels, T. M., Essop, M. F., & Joseph, D. E. (2024) · Viruses · doi:10.3390/v16081243 · Cited by 12
“Cells combat this viral infectivity toward adjacent cells by decreasing the amount of ACE2 on their surfaces [86].”
BackgroundPacnejer, A.-M., Butucă, A., Dobrea, C. M., Arseniu, A. M., Frum, A., Gligor, F. G., Arseniu, R., Vonica, R. C., Vonica-Țincu, A. L., Oancea, C. I., et al. (2024) · Viruses · doi:10.3390/v16121811 · Cited by 8
Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs)
McCarthy, C. G., Saha, P., Golonka, R. M., Wenceslau, C. F., Joe, B., & Vijay–Kumar, M. (2021) · Comprehensive physiology · doi:10.1002/j.2040-4603.2021.tb00163.x · Cited by 7
“After SARS-CoV-2 enters the host and infection subsequently ensues, this is associated with down-regulation of ACE2 expression and activity (76, 158, 215).”
Li, X., Fu, Y., Yu, T., Song, R., Nie, H., & Ding, Y. P. (2025) · Pharmaceuticals · doi:10.3390/ph18091329 · Cited by 7
“The host cell surface ACE2 receptor exhibits high expression levels in the lung, which is key to the life cycle of SARS-CoV-2 [90].”
Diabetic cardiomyopathy and COVID-19: intersecting pathways and amplified cardiovascular risk
Prakash, S., Choudhury, P., & Bisht, S. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1683159 · Cited by 7
Targeting SIRT1: A Potential Strategy for Combating Severe COVID‐19
Afra, H. S., Jeyvan, F. S., Barartabar, Z., Khanicheragh, P., Abdolmaleki, E. Y., Ilbeigi, D., Musavi, H., & Malekzadegan, Y. (2025) · BioMed Research International · doi:10.1155/bmri/9507417 · Cited by 7
Skin ulcer at the injection site of BNT162b2 mRNA COVID‐19 vaccine
Aoki, N., Saruta, Y., Tanaka, S., NAKAJIMA, R., Sano, H., & Sano, S. (2021) · The Journal of Dermatology · doi:10.1111/1346-8138.16163 · Cited by 7
Wade, H., Duan, Q., & Su, Q. (2022) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2022.05.010 · Cited by 8
COVID-19 and Thrombosis: Clinical Aspects
Urano, T., Yasumoto, A., Yokoyama, K., Horiuchi, H., Morishita, E., & Suzuki, Y. (2022) · Current Drug Targets · doi:10.2174/1389450123666221005092350 · Cited by 7
SARS-CoV-2 spike protein reduces burst activities in neurons measured by micro-electrode arrays
Salvador, M., Tseng, N., Park, C., Williams, G., Vethan, A., Thomas, G., Baker, J., Hemry, J., Hammond, E., Freeburg, P., et al. (2023) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000000950 · Cited by 7
“There is no known mechanism for chronic post-COVID, only a theorized list of potential contributors such as post-COVID infection, organ damage, chronic inflammation, which may be caused by impaired ACE2 receptors, and traumatic effects of being in critical care([31]).”
BackgroundSideratou, C.-M., & Papaneophytou, C. P. (2024) · Infectious Disease Reports · doi:10.3390/idr16040042 · Cited by 7
“This downregulation disrupts vasoregulation, potentially resulting in heightened vascular inflammation and coagulation abnormalities [46,47].”
BackgroundBlood Targets of Adjuvant Drugs Against COVID19
Micco, P. D., Micco, G. D., Russo, V., Poggiano, M. R., Salzano, C., Bosevski, M., Imparato, M., Fontanella, L., & Fontanella, A. (2020) · Journal of Blood Medicine · doi:10.2147/jbm.s256121 · Cited by 7
Manning, J. T., & Fink, B. (2020) · Early Human Development · doi:10.1016/j.earlhumdev.2020.105161 · Cited by 7
“The ACE2 → angiotensin1–7 → Mas receptor axis accomplishes the conversion of angiotensin II to the vasodilator angiotensin1–7 [7].”
BackgroundCardiovascular risk in COVID-19 infection.
Lubrano, V., & Balzan, S. (2020) · PubMed Central · Cited by 7
Pathogenesis of the initial stages of severe COVID-19
Голота, А. С., Kamilova, Т. A., Shneider, O. V., Vologzhanin, D. A., & Sherbak, S. G. (2021) · Journal of clinical practice · doi:10.17816/clinpract71351 · Cited by 7
“Низкая экспрессия ACE2, вызванная различными причинами (пожилой возраст, диабет, гипертония), увеличивает тяжесть инфекции SARS-CoV-2 [35].”
Ramana, C. V., & Das, B. (2021) · Computational and Mathematical Biophysics · doi:10.1515/cmb-2020-0128 · Cited by 7
Zappa, M., Verdecchia, P., Spanevello, A., & Angeli, F. (2022) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2022.08.012 · Cited by 7
“Since Ang1,7 exert anti-inflammatory, antithrombotic and vasodilating effects, the ascendency of Ang II over Ang1–7 might contribute to trigger inflammation, thrombosis and vasoconstriction [7,8].”
Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension: A Risk Factor for COVID-19
Govender, N., Khaliq, O. P., Moodley, J., & Naicker, T. (2022) · Current Hypertension Reviews · doi:10.2174/1573402118666220816090809 · Cited by 8
Severino, P., D’Amato, A., Prosperi, S., Myftari, V., Francia, A. L., Önkaya, M., Notari, C., Papisca, I., Canuti, E. S., Revivo, M. Y., et al. (2022) · Nutrients · doi:10.3390/nu14163439 · Cited by 7
Seth, P., & Sarkar, N. (2022) · 3 Biotech · doi:10.1007/s13205-022-03390-1 · Cited by 6
“Due to COVID, downregulation of ACE-2 receptors is noticed which results in microthrombosis of blood in the pulmonary environment (Fraga-Silva et al. 2008; Verdecchia et al. 2020).”
BackgroundSARS-CoV-2 leverages airway epithelial protective mechanism for viral infection
Greaney, A. M., Raredon, M. S. B., Kochugaeva, M. P., Niklason, L. E., & Levchenko, A. (2023) · iScience · doi:10.1016/j.isci.2023.106175 · Cited by 9
“75,76 ACE2 has also been found to be protective from experimental acute lung injury and pulmonary inflammation, 62,77–79 which may further explain how loss of ACE2 during SARS-CoV-2 infection contributes to severe disease.”
Activation of the Interferon Pathway in Trophoblast Cells Productively Infected with SARS-CoV-2
Kallol, S., Martin-Sancho, L., Morey, R., Aisagbonhi, O., Pizzo, D., Meads, M., Chanda, S., & Soncin, F. (2023) · Stem Cells and Development · doi:10.1089/scd.2022.0255 · Cited by 5
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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