CoChat
Sign Up
Cited by 20Renin-Angiotensin System StudiesSARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research Studies

An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection

Open access
Devaux, Christian A., Camoin-Jau, Laurence·2022·Frontiers in Microbiology
DOI 10.3389/fmicb.2022.1042200PMC PMC9742611
Open this paper in CoChat — free accountOpen PDF

Abstract

It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled “ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome”), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients’ therapy.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fmicb.2022.1042200

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the heart, ACE2 has been reported to be expressed on cardiomyocytes, pericytes, and macrophages with lower expression on fibroblasts and endothelial cells.

    “In the heart, ACE2 has been reported to be expressed on cardiomyocytes, pericytes (cells present along the walls of capillaries), and macrophages with lower expression on fibroblasts and endothelial cells.”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [19]

    The “ACE2 tissue distribution in human” section reports ACE2 in cardiac cardiomyocytes and pericytes. It does not identify cardiac macrophages as expressing ACE2, and it describes expression in cardiac fibroblasts and endothelial cells as strong, not lower. No page number is available for this passage in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ACE2 on endothelial cells of the arteries, arterioles, and venules of the heart and kidney determines its ability to regulate vascular function and blood pressure.

    “ACE2 on endothelial cells of the arteries, arterioles, and venules of the heart and kidney determines its ability to regulate vascular function and blood pressure, as reviewed previously.”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 510 · Cited by 20

Research works printed but not linked: 61

  1. Advani, A., Kelly, D. J., Cox, A. J., White, K. E., Advani, S. L., Thai, K., et al. (2009). The (pro)renin receptor: site-specific and functional linkage to the vacuolar H+- ATPase in the kidney. Hypertension 54, 261-269. doi: 10.1161/ HYPERTENSIONAHA.109.128645 · DOI
  2. Agachan, B., Isbir, T., Yilmaz, H., and Akoglu, E. (2003). Angiotensin converting enzyme I/D, angiotensinogen T174M-M235T and angiotensin II type 1 receptor A1166C gene polymorphisms in Turkish hypertensive patients. Exp. Mol. Med. 35, 545-549. doi: 10.1038/emm.2003. · DOI
  3. Arthur, J. M., Forrest, J. C., Boehme, K. W., Kennedy, J. L., Owens, S., Herzog, C., et al. (2021). Development of ACE2 autoantibodies after SARSCoV-2 infection. PLoS One 16:e0257016. doi: 10.1371/journal.pone.025701 · DOI
  4. Blume, C., Jackson, C. L., Spalluto, C. M., Legebeke, J., Nazlamova, L., Conforti, F., et al. (2021). A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection. Nat. Genet. 53, 205-214. doi: 10.1038/s41588-020-00759 · DOI
  5. abd2985 · DOI · Paper page
  6. cvaa078 · DOI · Paper page
  7. Chen, Y. Y., Liu, D., Zhang, P., and Zhong, J. C. (2016). Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J. Hum. Hypertens. 30, 766-771. doi: 10.1038/jhh.2016. · DOI
  8. Ciceri, F., Beretta, L., Mara Scandroglio, A., Colombo, S., Landoni, G., Ruggeri, A., et al. (2020). Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit. Care Resusc. 22, 95-97. doi: 10.51893/2020. · DOI
  9. Cole-Jeffrey, C. T., Liu, M., Katovich, M. J., Raizada, M. K., and Shenoy, V. (2015). ACE2 and microbiota: emerging targets for cardiopulmonary disease therapy. J. Cardiovasc. Pharmacol. 66, 540-550. doi: 10.1097/FJC.0000000000000307 · DOI
  10. Dahlbäck, B., and Villoutreix, B. O. (2005). Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition Arterioscler. Thromb. Vasc. Biol. 25, 1311-1320. doi: 10.1161/01.ATV.0000168421.13467. · DOI
  11. Davis, J. O., and Freeman, R. H. (1976). Mechanisms regulating renin release. Physiol. Rev. 56, 1-56. doi: 10.1152/physrev.1976.56.1. · DOI
  12. Epelman, S., Tang, W. H., Chen, S. Y., Lente, F. V., Francis, G. S., Sen, S., et al. (2008). Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin- aldosterone system. J. Am. Coll. Cardiol. 52, 750-754. doi: 10.1016/j.jacc.2008.02.088 · DOI
  13. Gheblawi, M., Wang, K., Viveiros, A., Nguyen, Q., Zhong, J. C., Turner, A. J., et al. (2020). Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ. Res. 126, 1456-1474. doi: 10.1161/CIRCRESAHA.120.317015 · DOI · Paper page
  14. Gjymishka, A., Kulemina, L. V., Shenoy, V., Katovich, M. J., Ostrov, D. A., and Raizada, M. K. (2010). Diminazene aceturate is an ACE2 activator and a novel antihypertensive drug. FASEB J. 24:1032. doi: 10.1096/fasebj.24.1_ supplement.1032. · DOI
  15. Goldblatt, H., Lynch, J., Hanzal, R. F., and Summerville, W. W. (1934). Studies on experimental hypertension: I. the production of persistent elevation of systolic blood pressure by means of renal ischemia. J. Exp. Med. 59, 347-379. doi: 10.1084/ jem.59.3.347 · DOI
  16. Goujon, C, Rebendenne, A, Roy, P, Bonaventure, B, Valadao, AC, Desmarets, L, et al. (2021). Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs. Research Square [Preprint]. doi: 10.21203/rs.3.rs-555275/v1 · DOI
  17. Greenberg, B. (2008). An ACE in the hole alternative pathways of the renin angiotensin system and their potential role in cardiac remodeling. J. Am. Coll. Cardiol. 52, 755-757. doi: 10.1016/j.jacc.2008.04.059 · DOI
  18. Hamming, I., Timens, W., Bulthuis, M., Lely, T., Navis, G., and van Goor, H. (2004). Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. J. Pathol. 203, 631-637. doi: 10.1002/path.1570 · DOI · Paper page
  19. Harrap, S. B., Tzourio, C., Cambien, F., Poirier, O., Raoux, S., Chalmers, J., et al. (2003). The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. Hypertension 42, 297-303. doi: 10.1161/01.HYP.0000088322.85804. · DOI
  20. Heeneman, S., Haendeler, J., Saito, Y., Ishida, M., and Berk, B. C. (2000). Angiotensin II induces transactivation of two different populations of the platelet- derived growth factor beta receptor. Key role for the p66 adaptor protein Shc. J. Biol. Chem. 275, 15926-15932. doi: 10.1074/jbc. · DOI
  21. M909616199 · DOI
  22. Hofman, P., Copin, M. C., Tauziede-Espariat, A., Adle-Biassette, H., Fortarezza, F., Passeron, T., et al. (2021). Histopathological features due to the SARS-CoV-2 [in French]. Ann. Pathol. 41, 9-22. doi: 10.1016/j.annpat.2020.1 2.009 · DOI
  23. Jackman, H. L., Massad, M. G., Sekosan, M., Tan, F., Brovkovych, V., Marcic, B. M., et al. (2002). Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin a. Hypertension 39, 976-981. doi: 10.1161/01.HYP.0000017283.67962. · DOI
  24. Karaderi, T., Bareke, H., Kunter, I., Seytanoglu, A., Cagnan, I., Balci, D., et al. (2020). Host genetics at the intersection of autoimmunity and COVID-19: a Devaux and Camoin-Jau 10.3389/fmicb.2022.1042200 Frontiers in Microbiology 31 frontiersin.org potential key for heterogeneous COVID-19 severity. Front. Immunol. 11:586111. doi: 10.3389/fimmu.2020.586111 · DOI
  25. Khayat, AS, de Assumpc, PP, Meireles Khayat, BC, Thomaz Arau Jo, TM, Batista-Gomes, JA, Imbiriba, L.C., et al. (2020). ACE2 polymorphisms as potential players in COVID-19 outcome. PLoS One 15:e0243887. doi: 10.1371/journal. pone.024388 · DOI
  26. Kliche, J., Kuss, H., Ali, M., and Ivarsson, Y. (2021). Cytoplasmic short linear motifs in ACE2 and integrin B3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy. Sci. Signal. 14:ebaf1117. doi: 10.1126/scisignal. · DOI
  27. abf1117 · DOI
  28. Lamers, M. M., Beumer, J., van der Vaart, J., Knoops, K., Puschhof, J., Breugem, T. I., et al. (2020). SARS-CoV-2 productively infects human gut enterocytes. Science 369, 50-54. doi: 10.1126/science. · DOI · Paper page
  29. abc1669 · DOI · Paper page
  30. Li, Z., and Ferguson, A. V. (1993). Subfornical organ efferents to paraventricular nucleus utilize angiotensin as a neurotransmitter. Am. J. Phys. Regul. Integr. Comp. Phys. 265, R302-R309. doi: 10.1152/ajpregu.1993.265. · DOI
  31. Luther, J. M., Gainer, J. V., Murphey, L. J., Yu, C., Vaughan, D. E., Morrow, J. D., et al. (2006). Hypertension 48, 1050-1057. doi: 10.1161/01.HYP.0000248135.97380. · DOI
  32. Manne, B. K., Denorme, F., Middleton, E. A., Portier, I., Rowley, J. W., Stubben, C. J., et al. (2020). Platelet gene expression and function in COVID-19 patients. Blood 136, 1317-1329. doi: 10.1182/-blood.2020007214 · DOI
  33. Martinez-Rojas, M. A., Vega-Vega, O., and Bobadilla, X. N. A. (2020). Is the kidney a target of SARS-CoV-2? Am. J. Physiol. Ren. Physiol. 318, F1454-F1462. doi: 10.1152/AJPRENAL.00160. · DOI
  34. Massiéra, F., Bloch-Faure, M., Ceiler, D., Murakami, K., Fukamizu, A., Gasc, J.-M., et al. (2001). Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J. 15, 2727-2729. doi: 10.1096/fj.01 · DOI
  35. Montagutelli, X, Prot, M, Levillayer, L, Baquero SAlazar, E, Jouvion, G, Conquet, L., et al. The B1.351 and P. 1 variants extend SARS-CoV-2 host range to mice. bioRxiv [Preprint]. (2021). doi: 10.1101/2021.03.18.436013 · DOI
  36. Muller, D. N., Mervaala, E. M. A., Dechend, R., Fiebeler, A., Park, J. K., Schmidt, F., et al. (2000). Angiotensin II (AT 1 ) receptor blockade reduces vascular tissue factor Devaux and Camoin-Jau 10.3389/fmicb.2022.1042200 Frontiers in Microbiology 33 frontiersin.org in angiotensin II-induced cardiac vasculopathy. Am. J. Pathol. 157, 111-122. doi: 10.1016/S0002-9440(10)64523-3 · DOI
  37. Naftilan, A. J., and Oparil, S. (1978). Inhibition of renin release from rat kidney slices by the angiotensins. Am. J. Phys. 235, F62-F68. doi: 10.1152/ ajprenal.1978.235. · DOI
  38. F62 · DOI
  39. Nemerson, Y. (1988). Tissue factor and hemostasis. Blood 71, 1-8. doi: 10.1182/ blood.V71.1.1. · DOI
  40. Oarhe, C. I., Dang, V., Dang, M. T., Nguyen, H., Gopallawa, I., Gewolb, I. H., et al. (2015). Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. Pediatr. Res. 77, 656-662. doi: 10.1038/pr.2015. · DOI
  41. Pires de Souza, G. A., Osman, I. O., Le Bideau, M., Baudoin, J.-P., Jaafar, R., Devaux, C., et al. (2022). Angiotensin II receptor blockers (ARBs antihypertensive Devaux and Camoin-Jau 10.3389/fmicb.2022.1042200 Frontiers in Microbiology 34 frontiersin.org agents) increase replication of SARS-CoV-2 in Vero E6 cells. Front. Cell. Infect. Microbiol. 11:639177. doi: 10.3389/fcimb.2021.639177 · DOI
  42. Procko, E. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2. bioRxiv [Preprint]. (2020). doi: 10.1101/2020.1103. 1116.994236 · DOI
  43. Rice, G. I., Jones, A. L., Grant, P. J., Carter, A. M., Turner, A. J., and Hooper, N. M. (2006). Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 48, 914-920. doi: 10.1161/01.HYP.0000244543.91937. · DOI
  44. Sadoshima, J., Qiu, Z. H., Morgan, J. P., and Izumo, S. (1995). Angiotensin-II and other hypertrophic stimuli mediated by G-protein-coupled receptors activate tyrosine kinase, mitogen-activated protein-kinase, and 90-Kd S6 kinase in cardiac myocytes -the critical role of Ca2+-dependent signaling. Circ. Res. 76, 1-15. doi: 10.1161/01.res.76.1. · DOI
  45. Sayed-Tabatabaei, F. A., Oostra, B. A., Isaacs, A., van Duijn, C. M., and Witteman, J. C. M. (2006). ACE polymorphism. Circ. Res. 98, 1123-1133. doi: 10.1161/01.RES.0000223145.74217. · DOI
  46. Singh, K. D., and Karnik, S. S. (2016). Angiotensin receptors: structure, function, signaling and clinical applications. J. Cell Signal. 1:111. doi: 10.4172/jcs.1000111 · DOI
  47. Tipnis, S. R., Hooper, N. M., and Hyde, R. (2000). A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril- insensitive carboxypeptidase. J. Biol. Chem. 275, 33238-33243. doi: 10.1074/jbc. · DOI
  48. M002615200 · DOI
  49. Vaduganathan, M., Varden, O., Michel, T., McMurray, J. J. V., Pfeffer, M. A., and Solomon, S. D. (2020). Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N. Engl. J. Med. 382, 1653-1659. doi: 10.1056/NEJMsr2005760 Devaux and Camoin-Jau 10.3389/fmicb.2022.1042200 Frontiers in Microbiology 36 frontiersin.org · DOI · Paper page
  50. Velkoska, E., Patel, S. K., and Burrell, L. M. (2016). Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation. Curr. Opin. Nephrol. Hypertens. 25, 384-395. doi: 10.1097/MNH.0000000000000254 · DOI
  51. Verdecchia, P., Angeli, F., Mazzotta, G., Gentile, G., and Reboldi, G. (2008). The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc. Health Risk Manag. 4, 971-981. doi: 10.2147/vhrm. · DOI
  52. s3215 · DOI
  53. Watanabe, T., Barker, T. A., and Berk, B. C. (2005). Angiotensin II and the endothelium: diverse signals and effects. Hypertension 45, 163-169. doi: 10.1161/01. HYP.0000153321.13792. · DOI
  54. Xiao, M., Zhang, Y., Zhang, S., Qin, X., Xia, P., Cao, W., et al. (2020). Anti- phospholipid antibodies in critically ill patients with coronavirus disease 2019 (COVID-19). Arthritis Rheum. 72, 1998-2004. doi: 10.1002/art.41425 · DOI
  55. Yang, P., Gu, H., Zhao, Z., Wang, W., Cao, B., Lai, C., et al. (2014). Angiotensin- converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci. Rep. 4:7027. doi: 10.1038/srep07027 Devaux and Camoin-Jau 10.3389/fmicb.2022.1042200 Frontiers in Microbiology 37 frontiersin.org · DOI · Paper page
  56. Yim, H. E., and Yoo, K. H. (2008). Renin-angiotensin system-considerations for hypertension and kidney. Electrol. Blood Press. 6, 42-50. doi: 10.5049/ EBP.2008.6.1. · DOI
  57. Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., et al. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370:eabd4570. doi: 10.1126/science. · DOI · Paper page
  58. abd4570 · DOI · Paper page
  59. Zhang, X. J., Qin, J. J., Cheng, X., Shen, L., Zhao, Y. C., Yuan, Y., et al. (2020). In- hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab. 32, 176-187. doi: 10.1016/j. cmet.2020.06.015. · DOI
  60. Zhang, H., Wada, J., Hida, K., Tsuchiyama, Y., Hiragushi, K., Shikata, K., et al. (2001). Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J. Biol. Chem. 276, 17132-17139. doi: 10.1074/jbc. · DOI
  61. M006723200 · DOI

Authors
Devaux, C. A., & Camoin-Jau, L.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Devaux, Christian A.
ORCID
Devaux, Christian A.
Venue
Frontiers in Microbiology
Publisher
Frontiers Media SA
Published
2022-11-28
Volume
13
Pages
1042200-1042200
ISSN
1664-302X (ISSN-L)
DOI
10.3389/fmicb.2022.1042200
PMC
PMC9742611
OpenAlex
W4310237087
Cited by
20
References
510
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 10 · 2022: 1
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Agence Nationale de la Recherche
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
angiotensin-converting enzyme 2, SARS-CoV-2, COVID-19 pathophysiology, renin-angiotensin system, hypertension, genetic susceptibility, angiotensin II, cytokine storm, microvascular damage, vascular disease, coagulopathy, COVID-19 severity, COVID-19 treatment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review