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Review
. 2021 Dec 22:12:732690.
doi: 10.3389/fimmu.2021.732690. eCollection 2021.

Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

Keiji Kuba  1 , Tomokazu Yamaguchi  1 , Josef M Penninger  2   3
Affiliations
Review

Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

Keiji Kuba et al. Front Immunol. .

Abstract

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

Keywords: ACE2; ARDS; SARS-CoV-2; acute lung injuries; renin – angiotensin – aldosterone system.

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Conflict of interest statement

Author JMP is a shareholder of Apeiron Biologics which is developing soluble ACE2 (APN01) for COVID-19 therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
ACE2-mediated cell entry of SARS-CoV-2 and inhibition of virus infection by recombinant soluble ACE2 protein.
Figure 2
Figure 2
Schematic of the Renin-angiotensin system (RAS) and the central roles of ACE and ACE2. AT1 receptor, Angiotensin type 1 receptor; MAS, MAS1 Proto-Oncogene, G Protein-Coupled Receptor. The amino acid sequences of Angiotensin 1 (Ang I), Angiotensin II (Ang II), and Angiotenin 1-7 (Ang 1-7) are indicated.
Figure 3
Figure 3
Summary of genetic study of the roles of RAS components in severe ARDS in mice. Ang II, Angiotensin II; AT1R, Angiotensin type 1 receptor; AT2R, Angiotensin type 2 receptor.
Figure 4
Figure 4
Proposed role of the RAS and ACE2 in SARS-CoV-2 infection and subsequent pathogenesis of ARDS.
See this image and copyright information in PMC

References

    1. Turner AJ, Tipnis SR, Guy JL, Rice G, Hooper NM. ACEH/ACE2 Is a Novel Mammalian Metallocarboxypeptidase and a Homologue of Angiotensin-Converting Enzyme Insensitive to ACE Inhibitors. Can J Physiol Pharmacol (2002) 80(4):346–53. doi: 10.1139/y02-021 - DOI - PubMed
    1. Oudit GY. The Role of ACE2 in Cardiovascular Physiology. Trends Cardiovasc Med (2003) 13(3):93–101. doi: 10.1016/S1050-1738(02)00233-5 - DOI - PubMed
    1. Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. Trilogy of ACE2: A Peptidase in the Renin-Angiotensin System, a SARS Receptor, and a Partner for Amino Acid Transporters. Pharmacol Ther (2010) 128(1):119–28. doi: 10.1016/j.pharmthera.2010.06.003 - DOI - PMC - PubMed
    1. Kuba K, Imai Y, Penninger JM. Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases. Circ J (2013) 77:301–8. doi: 10.1253/circj.CJ-12-1544 - DOI - PubMed
    1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. . A Pneumonia Outbreak Associated With a New Coronavirus of Probable Bat Origin. Nature (2020) 579:270–3. doi: 10.1038/s41586-020-2012-7 - DOI - PMC - PubMed

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