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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SARS-CoV and SARS-CoV-2 cell entry results in downregulation of ACE2.
“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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“[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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“[34] 4.2.”
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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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“[45] After ovariectomy, female animals showed similar reactions as in males.”
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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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“[21] The pulmonary lesions induced by experimental SARSCov infection are less aggressive in ACE2-knockout mice than in wildtype mice.”
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“[17] Elevated circulating levels of soluble ACE2 are markers of different disease states characterized by increased activity of the renin-angiotensin system and associated with a worse prognosis.”
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“[50] These reactions are increased in ACE2 knockout mice.”
El‐Hashim, A. Z., Renno, W. M., Raghupathy, R., Abduo, H., Akhtar, S., & Benter, I. F. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01905.x · Cited by 154 · see citing works
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× · see citing works
“[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× · see citing works
“[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× · see citing works
“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 · see citing works
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× · see citing works
“[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× · see citing works
“[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× · see citing works
“[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 103 · cited 1× · see citing works
“[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.”
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 102 · cited 1× · see citing works
“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.”
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 101 · cited 1× · see citing works
“[18, 19] 4. ACE2: angels or devils?”
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 101 · cited 1× · see citing works
“[53] 6. Clinical characteristics of patients infected with SARS-CoV and SARS-CoV-2”
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× · see citing works
“[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 85 · see citing works
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× · see citing works
“[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× · see citing works
“[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× · see citing works
“[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 · see citing works
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× · see citing works
“[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× · see citing works
“[61-63] Several experimental and clinical studies indicate that ACE2 deficiency obtained through deletion or inhibition may be a causative factor for hypertension.”
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 41 · cited 1× · see citing works
“[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.”
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× · see citing works
“The ACE2→Angiotensin1-7→Mas receptor axis exerts anti-thrombotic effects [35-38].”
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 · see citing works
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 · see citing works
Li, Y., Li, Y., Li, G., Song, Y., & Gong, X. (2013) · PubMed · doi:10.3275/8951 · Cited by 32 · see citing works
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× · see citing works
“[80,83] It is hoped that the results of the above mentioned NCT04312009 and NCT04311177 trials will answer this question.”
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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 1,592 · see citing works
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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 · see citing works
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 626 · see citing works
“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 603 · see citing works
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications
McFadyen, J. D., Stevens, H., & Peter, K. (2020) · Circulation Research · doi:10.1161/circresaha.120.317447 · Cited by 592 · see citing works
Carlini, V., Noonan, D. M., Abdalalem, E., Goletti, D., Sansone, C., Calabrone, L., & Albini, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1161067 · Cited by 570 · see citing works
The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity
Osuchowski, M., Winkler, M., Skirecki, T., Cajander, S., Shankar-Hari, M., Lachmann, G., Monneret, G., Venet, F., Bauer, M., Brunkhorst, F., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00218-6 · Cited by 396 · see citing works
The COVID-19 pandemic: a global health crisis
Pollard, C., Morran, M. P., & Nestor‐Kalinoski, A. L. (2020) · Physiological Genomics · doi:10.1152/physiolgenomics.00089.2020 · Cited by 518 · see citing works
Bajaj, V., Gadi, N., Spihlman, A. P., Wu, S. C., Choi, C. H., & Moulton, V. R. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.571416 · Cited by 476 · see citing works
“A decrease in ACE2 expression has been reported in individuals with hypertension and diabetes (Li et al., 2020; Verdecchia et al., 2020) making them susceptible to increased inflammation via the angiotensin 2 pro-inflammatory pathway, while treatment with ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) t…”
BackgroundInfluentialOrgan-specific manifestations of COVID-19 infection
Gavriatopoulou, M., Korompoki, E., Fotiou, D., Ntanasis‐Stathopoulos, I., Ψαλτοπούλου, Θ., Kastritis, E., Terpos, E., & Dimopoulos, M. A. (2020) · Clinical and Experimental Medicine · doi:10.1007/s10238-020-00648-x · Cited by 497 · see citing works
“Importantly, the binding of SARS-CoV-2 to ACE2 is anticipated to result in loss of the external ACE2 catalytic effect [63, 64].”
BackgroundCOVID-19 cytokine storm: the anger of inflammation
Mahmudpour, M., Roozbeh, J., Keshavarz, M., Farrokhi, S., & Nabipour, I. (2020) · Cytokine · doi:10.1016/j.cyto.2020.155151 · Cited by 461 · see citing works
“Because Ang-(1–7) exerts a critical role in counteracting the pro-inflammatory effect of RAAS, protecting from endothelial cell activation and resulting lung damage from inflammatory mediators in the cytokine storm, the administration of Ang(1–7) or one of its similar agents to patients with COVID-19 pneumonitis has b…”
COVID-19 and multiorgan failure: A narrative review on potential mechanisms
Mokhtari, T., Hassani, F., Ghaffari, N., Ebrahimi, B., Yarahmadi, A., & Hassanzadeh, G. (2020) · Journal of Molecular Histology · doi:10.1007/s10735-020-09915-3 · Cited by 440 · see citing works
“Attachment of the virus to ACE2 and invasion of host cells can directly infect them and increase the inflammatory responses and consequently lead to the cell death and lung complications (Verdecchia et al. 2020).”
BackgroundChest CT in COVID-19: What the Radiologist Needs to Know
Kwee, T. C., & Kwee, R. M. (2020) · Radiographics · doi:10.1148/rg.2020200159 · Cited by 437 · see citing works
“(10) Findings classified as indeterminate appearance of COVID-19 pneumonia according to the RSNA chest CT classification system (51) in a 24-year-old woman.”
BackgroundMethodFabiani, L., Saroglia, M. G., Galatà, G., Santis, R. D., Fillo, S., Luca, V., Faggioni, G., D’Amore, N., Regalbuto, E., Salvatori, P., et al. (2020) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2020.112686 · Cited by 434 · see citing works
“S protein is cleaved by a host cell furin-like protease into two separate polypeptides S1 and S2 and it is characterized by an affinity with the human angiotensin-converting enzyme 2 (hACE2) used as a receptor to infect human cells (Verdecchia et al., 2020; Xia et al., 2020).”
BackgroundAfzal, S., Manap, A. S. A., Attiq, A., Albokhadaim, I. F., Kandeel, M. K., & Alhojaily, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1269581 · Cited by 423 · see citing works
Targeting the NLRP3 Inflammasome in Severe COVID-19
Freeman, T. L., & Swartz, T. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01518 · Cited by 406 · see citing works
“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
Higgins, V., Sohaei, D., Diamandis, E. P., & Prassas, I. (2020) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2020.1860895 · Cited by 414 · see citing works
“into cells via membrane fusion leads to downregulation of ACE2 and subsequent loss of their catalytic ability to degrade angiotensin II [9].”
BackgroundObesity ‑ a risk factor for increased COVID‑19 prevalence, severity and lethality (Review)
Petrakis, D., Margina, D. M., Tsarouhas, K., Tekos, F., Stan, M., Nikitovic, D., Kouretas, D., Spandidos, D. A., & Tsatsakis, A. M. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11127 · Cited by 388 · see citing works
Fotuhi, M., Mian, A., Meysami, S., & Raji, C. A. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200581 · Cited by 388 · see citing works
“ACE2 deficiency lessens the impact of SARS-Cov2 infection [32].”
BackgroundInfluentialYu, J. M., Yuan, X., Chen, H., Chaturvedi, S., Braunstein, E. M., & Brodsky, R. A. (2020) · Blood · doi:10.1182/blood.2020008248 · Cited by 375 · see citing works
Covid‐19 and kidney injury: Pathophysiology and molecular mechanisms
Ahmadian, E., Khatibi, S. M. H., Soofiyani, S. R., Abediazar, S., Shoja, M. M., Ardalan, M., & Vahed, S. Z. (2020) · Reviews in Medical Virology · doi:10.1002/rmv.2176 · Cited by 366 · see citing works
“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.”
BackgroundVitamin D, infections and immunity
Ismailova, A., & White, J. H. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09679-5 · Cited by 354 · see citing works
A Guide to COVID‐19: a global pandemic caused by the novel coronavirus SARS‐CoV‐2
Atzrodt, C. L., Maknojia, I. H., McCarthy, R. D. P., Oldfield, T. M., Po, J., Ta, K. T. L., Stepp, H. E., & Clements, T. P. (2020) · FEBS Journal · doi:10.1111/febs.15375 · Cited by 350 · see citing works
Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review
Suhail, S., Zajac, J. W. P., Fossum, C. J., Lowater, H. R., McCracken, C. N., Severson, N. J., Laatsch, B. F., Narkiewicz-Jodko, A., Johnson, B., Liebau, J., et al. (2020) · The Protein Journal · doi:10.1007/s10930-020-09935-8 · Cited by 310 · see citing works
“It activates angiotensin, a regulator of blood pressure, and binds to the cell membranes of tissues in the lungs, heart, kidneys, intestinal cells, brain, and testes [33].”
BackgroundInfluentialEndothelial dysfunction in COVID-19: Current findings and therapeutic implications
Nägele, M. P., Haubner, B. J., Tanner, F. C., Ruschitzka, F. T., & Flammer, A. J. (2020) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2020.10.014 · Cited by 300 · see citing works
COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation
Kempuraj, D., Selvakumar, G. P., Ahmed, M. E., Raikwar, S. P., Thangavel, R., Khan, A. C., Zaheer, S. A., Iyer, S. S., Burton, C., James, D., et al. (2020) · The Neuroscientist · doi:10.1177/1073858420941476 · Cited by 294 · see citing works
COVID-19, Renin-Angiotensin System and Endothelial Dysfunction
Amraei, R., & Rahimi, N. (2020) · Cells · doi:10.3390/cells9071652 · Cited by 275 · see citing works
“SARS-CoV-2 entry via ACE2 causes downregulation of membrane-bound ACE2 and concurrent loss of catalytic activity of ACE2 in the RAS system [100].”
BackgroundThrombosis in Coronavirus disease 2019 (COVID-19) through the prism of Virchow’s triad
Ahmed, S., Zimba, O., & Gasparyan, A. Y. (2020) · Clinical Rheumatology · doi:10.1007/s10067-020-05275-1 · Cited by 251 · see citing works
Islam, M. S., Aziz, M. A., Aziz, M. A., Aka, T. D., & Jakaria, M. (2020) · Heliyon · doi:10.1016/j.heliyon.2020.e05684 · Cited by 245 · see citing works
“SARS-CoV-2 binds with the ACE-2 receptor, causing diffuse alveolar damage and lymphocytic infiltration in both lungs and may cause several respiratory tract symptoms [100].”
Wuhan to World: The COVID-19 Pandemic
Kumar, A., Singh, R. G., Kaur, J., Pandey, S., Sharma, V., Thakur, L., Sati, S., Mani, S., Asthana, S., Sharma, T. K., et al. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.596201 · Cited by 241 · see citing works
“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).”
BackgroundCognitive impact of COVID-19: looking beyond the short term
Miners, J. S., Kehoe, P. G., & Love, S. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00744-w · Cited by 248 · see citing works
“This mechanism has also been proposed to explain other vascular and pulmonary manifestations of COVID-19 [135, 136].”
BackgroundNeurological and Neuropsychiatric Impacts of COVID-19 Pandemic
Roy, D., Ghosh, R., Dubey, S., Dubey, M. J., Benito‐León, J., & Ray, B. K. (2020) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/cjn.2020.173 · Cited by 228 · see citing works
COVID-19 and thrombosis: From bench to bedside
Ali, M. A., & Spinler, S. A. (2020) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2020.12.004 · Cited by 209 · see citing works
de Erausquin, G. A., Snyder, H. M., Carrillo, M. C., Hosseini, A. A., Brugha, T. S., & Seshadri, S. S. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12255 · Cited by 193 · see citing works
Gadi, N., Wu, S., Spihlman, A. P., & Moulton, V. R. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02147 · Cited by 185 · see citing works
“Viral entry into a cell causes downregulation of ACE2, which may be detrimental in patients already deficient in ACE2 (116).”
BackgroundPeptide and peptide-based inhibitors of SARS-CoV-2 entry
Schütz, D., Ruiz‐Blanco, Y. B., Münch, J., Kirchhoff, F., Sánchez‐García, E., & Müller, J. A. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.11.007 · Cited by 179 · see citing works
“The coronaviruses SARS-CoV-1, HCoV-NL63 and SARS-CoV-2 utilize ACE2 as entry receptor [58].”
Comparative ACE2 variation and primate COVID-19 risk
Melin, A. D., Janiak, M. C., Marrone, F., Arora, P. S., & Higham, J. P. (2020) · Communications Biology · doi:10.1038/s42003-020-01370-w · Cited by 178 · see citing works
Davidson, A. M., Wysocki, J. A., & BATLLE, D. C. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.15256 · Cited by 180 · see citing works
COVID-19 and Respiratory System Disorders
Brosnahan, S. B., Jonkman, A. H., Kugler, M. C., Munger, J. S., & Kaufman, D. A. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314515 · Cited by 179 · see citing works
Resveratrol Inhibits HCoV-229E and SARS-CoV-2 Coronavirus Replication In Vitro
Pasquereau, S., Nehme, Z., Ahmad, S. H., Daouad, F., Assche, J. V., Wallet, C., Schwartz, C., Rohr, O., Morot-Bizot, S., & Herbein, G. (2021) · Viruses · doi:10.3390/v13020354 · Cited by 177 · see citing works
“Increase in the ACE2/Ang1-7/MasR axis has been reported to reduce hyperinflammation in Covid-19 patients [44].”
BackgroundKörner, R. W., Majjouti, M., Alcazar, M. A. A., & Mahabir, E. (2020) · Viruses · doi:10.3390/v12080880 · Cited by 178 · see citing works
Viral Infections, the Microbiome, and Probiotics
Harper, A., Vijayakumar, V., Ouwehand, A. C., ter Haar, J., Obis, D., Espadaler, J., Binda, S., Desiraju, S., & Day, R. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.596166 · Cited by 177 · see citing works
“Moreover, four specific bacteria (Bacteroides dorei, February 2021 | Volume 10 | Article 596166 Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus), known to downregulate ACE2 expression in the murine colon, were inversely correlated with SARS-CoV-2 mRNA load in feces (Zuo et al., 2020).”
BackgroundInfluentialSARS-CoV-2, ACE2 expression, and systemic organ invasion
Ashraf, U., Abokor, A. A., Edwards, J. M., Waigi, E. W., Royfman, R., Hasan, S. A., Smedlund, K., Grégio, A. M. T., Chakravarti, R., & Koch, L. G. (2020) · Physiological Genomics · doi:10.1152/physiolgenomics.00087.2020 · Cited by 173 · see citing works
Farsalinos, K. E., Barbouni, A., Poulas, K. A., Polosa, R., Caponnetto, P., & NIAURA, R. S. (2020) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622320935765 · Cited by 171 · see citing works
COVID-19–Associated Nonocclusive Fibrin Microthrombi in the Heart
Bois, M. C., Boire, N. A., Layman, A. J., Aubry, M.-C., Alexander, M. P., Roden, A. C., Hagen, C. E., Quinton, R. A., Larsen, C. P., Erben, Y., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.050754 · Cited by 163 · see citing works
McGonagle, D., Marco, G. D., & Bridgewood, C. (2021) · Journal of Autoimmunity · doi:10.1016/j.jaut.2021.102662 · Cited by 165 · see citing works
“Furthermore, a strong rationale for SARS-CoV-2 spike-protein-mediated downregulation of endothelial ACE2 receptor expression that predisposes to vasospasm and immunothrombosis has been put forward [16].”
BackgroundRamarao, P., Joshi, G., & Jagadeesh, G. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109721 · Cited by 155 · see citing works
Bacterial infections and patterns of antibiotic use in patients with COVID‐19
Neto, A. G. M., Lo, K. B., Wattoo, A., Salacup, G., Pelayo, J., DeJoy, R., Bhargav, R., Gul, F., Peterson, E. L., Albano, J., et al. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26441 · Cited by 151 · see citing works
“A c c e p te d A r ti c le viral intracellular inoculation resulting in more cellular pyroptosis.(26-28) Combination of chronic proinflammatory state and higher cellular pyroptosis by COVID-19 predispose these patients with cardiometabolic comorbidities to an amplified cytokine storm.”
BackgroundMonocytes and macrophages in COVID-19: Friends and foes
Meidaninikjeh, S., Sabouni, N., Marzouni, H. Z., Bengar, S., Khalili, A., & Jafari, R. (2021) · Life Sciences · doi:10.1016/j.lfs.2020.119010 · Cited by 151 · see citing works
“This could induce the pathogenesis of SARS-CoV-2 through ARDS in the patients with COVID-19 that has been reported as a severity manifestation of current infection [119,120].”
BackgroundInfluentialMunavalli, G. G., Guthridge, R., Knutsen-Larson, S., Brodsky, A., Matthew, E. J., & Landau, M. (2021) · Archives of Dermatological Research · doi:10.1007/s00403-021-02190-6 · Cited by 148 · see citing works
Wijeratne, T., & Crewther, S. G. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.117179 · Cited by 146 · see citing works
Risk Factors for Hospitalization and Mortality due to COVID-19 in Espírito Santo State, Brazil
Soares, R. D. C. M., Mattos, L. R., & Raposo, L. M. (2020) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.20-0483 · Cited by 144 · see citing works
Is there a smoker’s paradox in COVID-19?
Usman, M., Siddiqi, T. J., Khan, M. S., Patel, U. K., Shahid, I., Ahmed, J., Kalra, A., & Michos, E. D. (2020) · BMJ Evidence-Based Medicine · doi:10.1136/bmjebm-2020-111492 · Cited by 145 · see citing works
Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells?
Gadanec, L. K., McSweeney, K. R., Qaradakhi, T., Ali, B. A., Zulli, A., & Apostolopoulos, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22030992 · Cited by 145 · see citing works
Omega 3 Fatty Acids and COVID-19: A Comprehensive Review
Hathaway, D., Pandav, K. B., Patel, M., Riva-Moscoso, A., Singh, B. M., Patel, A., Min, Z. C., Makkar, S. S., Sana, M. K., Sanchez-Dopazo, R., et al. (2020) · Infection and Chemotherapy · doi:10.3947/ic.2020.52.4.478 · Cited by 142 · see citing works
“ACE-2 receptors are the receptors that mediate the viral entry of SARS-CoV-2, causing vasoconstriction, inflammation, and thrombosis [17, 24].”
BackgroundShirbhate, E., Pandey, J., Patel, V. K., Kamal, M., Jawaid, T., Gorain, B., Kesharwani, P., & Rajak, H. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00303-6 · Cited by 149 · see citing works
Efforts at COVID-19 Vaccine Development: Challenges and Successes
Haque, A., & Pant, A. B. (2020) · Vaccines · doi:10.3390/vaccines8040739 · Cited by 139 · see citing works
“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 137 · see citing works
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 · see citing works
“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 · see citing works
Epigenetic mechanisms regulating COVID-19 infection
Chlamydas, S., Papavassiliou, A. G., & Piperi, C. (2020) · Epigenetics · doi:10.1080/15592294.2020.1796896 · Cited by 134 · see citing works
“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 133 · see citing works
“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 · see citing works
Annasamy, G., Kumar, N. A., & Anand, S. (2021) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2021.116205 · Cited by 129 · see citing works
Farshbafnadi, M., Zonouzi, S. K., Sabahi, M., Dolatshahi, M., & Aarabi, M. H. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111507 · Cited by 124 · see citing works
“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 125 · see citing works
“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 127 · see citing works
“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 122 · see citing works
“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 121 · see citing works
“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 117 · see citing works
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 · see citing works
“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 116 · see citing works
“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 120 · see citing works
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 110 · see citing works
“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 112 · see citing works
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 113 · see citing works
“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 110 · see citing works
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 114 · see citing works
“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 · see citing works
“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 105 · see citing works
“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 103 · see citing works
Pei, R., Feng, J.-Q., Zhang, Y., Sun, H., Li, L., Yang, X., He, J.-P., Xiao, S., Xiong, J., Lin, Y., et al. (2020) · Protein & Cell · doi:10.1007/s13238-020-00811-w · Cited by 91 · see citing works
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 · see citing works
“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 · see citing works
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 102 · see citing works
Alam, M. S., & Czajkowsky, D. M. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.11.001 · Cited by 101 · see citing works
“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 · see citing works
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 103 · see citing works
“, 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 98 · see citing works
“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 · see citing works
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 94 · see citing works
“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 96 · see citing works
“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 · see citing works
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 · see citing works
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 99 · see citing works
“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…”
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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 94 · see citing works
“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 96 · see citing works
“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 91 · see citing works
- 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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