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Review
. 2021 Jun 23;22(13):6703.
doi: 10.3390/ijms22136703.

Do Changes in ACE-2 Expression Affect SARS-CoV-2 Virulence and Related Complications: A Closer Look into Membrane-Bound and Soluble Forms

Huseyin C Yalcin  1 , Vijayakumar Sukumaran  1 , Mahmoud Khatib A A Al-Ruweidi  1   2 , Samar Shurbaji  1
Affiliations
Review

Do Changes in ACE-2 Expression Affect SARS-CoV-2 Virulence and Related Complications: A Closer Look into Membrane-Bound and Soluble Forms

Huseyin C Yalcin et al. Int J Mol Sci. .

Abstract

The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states.

Keywords: ACE inhibitors; ACE-2; ARDS; COVID-19; RAAS; SARS-CoV; angiotensin receptor blockers; shedding.

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Conflict of interest statement

The author has no conflict of interest to declare with respect to this manuscript.

Figures

Figure 1
Figure 1
SARS-CoV’s viral invasion of the host cell via a membrane-bound ACE-2 receptor. ACE-2 mediates entry of coronavirus in two distinct ways. The first one is Clathrin and ADAM 17-dependent endocytosis, and the second one is TMPRSS2-dependent membrane fusion. Figure replicated from [6] with permission.
Figure 2
Figure 2
Organ-specific comparative ACE-2 expression. Figure replicated from [13] with permission.
Figure 3
Figure 3
Schematic diagram for the major pathways in RAAS.
Figure 4
Figure 4
ACE-2 shedding and SARS-CoV-2 entry. TMPRSS2 process ACE-2 for efficient viral entry and replication. Figure replicated from [12] with permission.
Figure 5
Figure 5
The RAAS with COVID-19. The thicker arrows show an increase in the degree of pathway activation; dotted arrows show a decrease in pathway activation. ACE: angiotensin-converting enzyme; ACE-2: angiotensin-converting enzyme-2; AT1R: angiotensin type 1 receptor; AT2R: angiotensin type2 receptor; ANG 1–7: angiotensin 1–7; ARB: angiotensin receptor blockers; rhACE-2: recombinant human ACE-2; TMPRSS2: transmembrane serine protease 2 (figure replicated from [46] with permission).
Figure 6
Figure 6
Working mechanisms for ACEi and ARB and relevance to SARS-CoV/SARS-CoV-2 infections. Figure replicated from [82] with permission.
Figure 7
Figure 7
Potential approaches against ARDS and adverse cardiac events relevant to SARS-CoV-2 infection.
See this image and copyright information in PMC

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