Talk:Angiotensin-converting enzyme 2

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Treatment with angiotensin-converting enzyme (ACE) inhibitors results in an upregulation of ACE2,[23]

Can anybody actually find that statement in reference 23? — Preceding unsigned comment added by 96.242.2.70 (talk) 23:20, 17 March 2020 (UTC)

Good point. I read the article twice but cannot find any such comment. This short paragraph is a paraphrase of a recent letter to the editor in Lancet, with the same references. I searched PubMed but did not find any clear evidence to support the statement. Valmataro (talk) 14:58, 18 March 2020 (UTC)

• Here is good review to be used on this page. My very best wishes (talk) 18:56, 20 March 2020 (UTC)

Thank you for the review but it also does not support the author claim from the Lancet article. I finally found this article describing that ACE inhibition does upregulate cardiac ACE2 mRNA expression in rats: Ferrario et al. 2005. — Preceding unsigned comment added by 96.242.2.70 (talk) 20:41, 23 March 2020 (UTC)

Is there a difference (in this context) between "ACE2" and "ACE2 receptor"?

Recent additions to this article indirectly claim that there is a difference between "ACE2" and "ACE2 receptor". I very much doubt this is the case. All the literature I have read on related subjects treat those terms interchangeably and/or describe them in the same terms.--Dpratt71 (talk) 16:52, 17 March 2020 (UTC)

ACE2 comes in 2 flavors. Membrane bound (designated mACE2) and soluble (sACE2).

If you don't mind me using analogies, think of the mACE2 as a docking port like you might find on a spaceship. When the docking port is attached to the ship (mACE2), other ships (COVID19) can dock to the port and gain access to the ship (the cell). If however, the docking port (mACE2) were to be cut away (or cleaved) from the ship giving us a free floating docking port (sACE2), other ships (COVID19) would not be able to dock to that ship (the cell). They would only be able to dock to those free floating docks (sACE2). Which would give them access to nothing and only serve to tie up that docking port (the S-spike protein on the COVID19 virus). Yaktam (talk) 08:00, 19 March 2023 (UTC)

"ACE2 receptor" makes no sense. ACE2 is ITSELF the receptor for SARS-CoV and SARS-CoV-2 on respiratory tract cells. In normal function, ACE2 = angiotensin converting enzyme 2 "catalyses the conversion of angiotensin I to the nonapeptide angiotensin[1–9][5] or the conversion of angiotensin II to angiotensin 1–7.[6][7]". --Canavalia (talk) 19:29, 17 March 2020 (UTC)

That was my understanding, thank you for confirming, Canavalia. To further clarify, I think the term "ACE2 receptor" makes sense, it's just a bit redundant. The "ACE2 receptor" is not a receptor for ACE2, ACE2 is the receptor, as you say. As such, I believe this statement in the article is in error and should be removed (along with any corresponding edits):

This might lead some to suggest that decreasing the levels of ACE2, in cells, might help in fighting the infection, but that conflates ACE2 with the ACE2 receptor.

I'd vastly prefer someone with more subject knowledge make that edit (or at least someone with more WP editing knowledge), but I may get up the nerve to do it otherwise. --Dpratt71 (talk) 18:15, 17 March 2020 (UTC)

Reply It seems like they're the same according to the reference provided that they're reliable. For instance, ACE inhibitor is literally Angiotensin-converting enzyme inhibitor.

There are some enzyme binding sites, alias receptor, on every enzyme though I am not confident in my answer.

Further information: Enzyme inhibitor

@Reciprocater: A substrate binding site on an enzyme should not be confused with a ligand binding site on a receptor. Those are two difference things. A few but not all enzymes also function as receptors. Boghog (talk) 11:57, 21 March 2020 (UTC)

Thank you, User:Boghog.--Reciprocater (talk) 12:41, 21 March 2020 (UTC)

References

@Seppi333: May I have your opinion on this？ Thank you!

--Reciprocater (talk) —Preceding undated comment added 14:42, 20 March 2020 (UTC)

Graham Beards is probably the best editor to ask about this. WhatamIdoing (talk) 15:45, 20 March 2020 (UTC)

They are the same molecule. Saying "ACE2 receptor" is shorthand for "the virus uses ACE-2 as the receptor". Graham Beards (talk) 15:53, 20 March 2020 (UTC)

Thank you User:Graham Beards for the answer. And which between receptor, enzyme and enzyme inhibitors do you think enzyme binding sites is best redirected to? Thanks again! --Reciprocater (talk) 16:09, 20 March 2020 (UTC) Graham Beards

I don't fully understand you but if you are discussing receptors for viruses the answer is none really. If any the receptor article seems the more appropriate but it doesn't mention receptors for viruses. HIV uses the CD4 and the chemokine receptor CCR5 for example. (Influenza virus uses an enzyme – neuraminidase – during viral release from the cell).Graham Beards (talk) 16:29, 20 March 2020 (UTC)

Thank you for the time. And since I've just really started learning English for 6-7 years, I appreciate your understanding of my incomprehensible English sentences. Orz Anyway, I think I am going to randomly redirect enzyme binding site to any of receptor, enzyme and enzyme inhibitor. People can then alter the redirection as they find fit. Best! --Reciprocater (talk) 16:37, 20 March 2020 (UTC)

I suggest taking a look at active site and binding site before you do that.Graham Beards (talk) 16:42, 20 March 2020 (UTC)

Thank you! I will take a look! I should've seen your kind reply earlier. (I was just deciding to take a rest after I had done redirecting....that's why I did it so quick...) --Reciprocater (talk) 16:45, 20 March 2020 (UTC)

Same protein can work as an enzyme (this is biological function of ACE2 in health) and a receptor for the virus (in context of viral entry). Therefore, in terms of WP categories, it belongs to the both. My very best wishes (talk) 17:08, 20 March 2020 (UTC)

To put it another way: one protein with two functions. Humans use the protein as an enzyme. Coronaviruses have hijacked this protein for use as a receptor. For other examples of dual use proteins, see protein moonlighting. Boghog (talk) 04:48, 21 March 2020 (UTC)

Reply ACE2 is the enzyme, while there is a surface protein on some cells that allows entry of ACE2 into the cell, the "receptor". They are very different things. Cells have receptors to allow entry of ACE2 for evolutionary biological processes. Certain viruses can and do co-opt that entry mechanism to gain entry to the cell. I don't have references to hand, this is what I have learned through listening to TWiV. Pete Miller.

Good ACE, bad ACE

The role of ACE2 in SARS-CoV and SARS-CoV-2 is complicated. The following about ACE in SARS (which should also apply equally to SARS-CoV-2) is clearest explanation I have been able to find:

• Nicholls J, Peiris M (August 2005). "Good ACE, bad ACE do battle in lung injury, SARS". Nature Medicine. 11 (8): 821–2. doi:10.1038/nm0805-821. PMID 16079870.

There are a number of things going on here:

• The normal function of ACE2 is to lower blood pressure by cleaving vasoconstricting angiotensin II to the vasodilating AT1–7 peptide.
• Coronavirus uses ACE2 as a cell surface receptor to gain entrance into the cell
• Binding of coronavirus to ACE2 down regulates the levels of ACE2 through internalization of ACE2 → angiotensin II↑ and AT1–7↓ → lung damage
• Both ACE inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression
• In terms of coronavirus infection, up regulation of ACE2 has potentially both bad and good effects:
  • bad: more receptors for coronavirus entry into cells
  • good: decrease angiotensin II and increase in AT1–7 which in turn protects lungs against damage

This has immediate implications for the continued use of blood pressure lower ACE inhibitors and ABRs in the environment of the coronavirus pandemic. The current recommendation is not to change standard prescribing practice. Boghog (talk) 06:15, 21 March 2020 (UTC)

In reading reference 28, and the corresponding research article that it talks about (https://www.nature.com/articles/nm1267), I could not find any data or reference saying ACE inhibitor drugs increase the expression of ACE2 receptor. The claim that ACE2 is increased, increasing the susceptibility to the novel SARS-CoV-2 virus is misleading. — Preceding unsigned comment added by 71.255.159.10 (talk) 16:20, 23 March 2020 (UTC)

The above bullet point summary was not completely sourced. My apologizes. According to the HFSA/ACC/AHA Statement "In a few experimental studies with animal models, both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart". I am not at all advocating it does or does not. I am just trying to put in context why the HFSA/ACC/AHA was compelled to issue their statement in the first place. Boghog (talk) 19:49, 23 March 2020 (UTC)

Plea for simplicity

Dear many authors of this page (Boghog, Valmataro, Reciprocater, John B123), I would like to please request, given the large number of page views that is received, that edits strive to make the content as understandable to the lay and non biomedically-trained reader as possible. This is the lead at the moment: Angiotensin converting enzyme 2 (ACE2, Angiotensin I converting enzyme 2)[5] is an enzyme expressed on the membrane of many cell types, including epithelial cells of the pulmonary alveolus and small intestine enterocytes.[6] It is an exopeptidase that catalyses the cleavage of angiotensin I into the nonapeptide angiotensin 1-9, and angiotensin II into angiotensin 1–7, which acts as a vasodilator.[7][8][9] ACE2 is a single-pass type I membrane protein.[10] It is also shed from cells and released into the blood stream and ultimately urine, by proteolytic cleavage.[11][12] The membrane-bound form of ACE2 serves as the entry point into human cells for some human coronaviruses. This is not understandable to lay editors!! Here are some examples of some methods things can be changed:

• Used a piped link so a more common word can be used: eg. pulmonary --> lung alveolus
• Use a more simple phrase so readers understand what you mean: "proteolytic cleavage" --> "cleavage of the protein"
• Use more words to separate concepts into separate clauses: "vasodilator angiotensin 1-7" --> "angiotentin 1-7, which acts as a vasodilator"
• See WP:ANATSIMPLIFY for more examples

Could editors please take readers into account when editing? It is possible to be both accurate and easy to read. Being "scientific" doesn't mean that it has to be incomprehensible; but the current state leaves the article only understandable to people with university level training, which is not ideal. Cheers --Tom (LT) (talk) 23:18, 21 March 2020 (UTC)

I fixed it a little, but you are welcome to continue. My very best wishes (talk) 02:18, 22 March 2020 (UTC)

• @Tom (LT): Hello, could you please clarify the statement in terms of what in your addition of {{what}} in Angiotensin-converting_enzyme_2#Human_recombinant_ACE2_(rhACE2)? I don't fully understand you. English is my second language. Thank you. --Reciprocater (Talk) 07:35, 30 March 2020 (UTC)
  • Sure. "Improves pulmonary haemodynamics" is an ambiguous term, analagous to me to something like "it makes velocity better" without given any indication of what part of pulmonary haemodynamics are improved, eg what is the influence on the flow of blood through the lungs and why is this an improvement? --Tom (LT) (talk) 07:39, 30 March 2020 (UTC)
    • Thanks. I gonna review the reference to confirm if such detail has provided. --Reciprocater (Talk) 07:43, 30 March 2020 (UTC)
    • , the cited primary source in the review. I am uncertain if it has provided the detail you're reffering to. I haven't had enough time to read it thoroughly. You're very welcome to have a read and add precious information to the article to enlighten us. Best. --Reciprocater (Talk) 08:31, 30 March 2020 (UTC)

References

Risk of penumonia associated with ARBs and ACEs .

The interaction of the spike protein of the coronavirus with ACE2 induces a drop in the levels of ACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.[18]

• Kuba, Keiji; Imai, Yumiko; Rao, Shuan; Gao, Hong; Guo, Feng; Guan, Bin; Huan, Yi; Yang, Peng; Zhang, Yanli; Deng, Wei; Bao, Linlin; Zhang, Binlin; Liu, Guang; Wang, Zhong; Chappell, Mark; Liu, Yanxin; Zheng, Dexian; Leibbrandt, Andreas; Wada, Teiji; Slutsky, Arthur S; Liu, Depei; Qin, Chuan; Jiang, Chengyu; Penninger, Josef M (2005-07-10). "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury". Nature medicine. 11 (8). Springer Science and Business Media LLC: 875–879. doi:10.1038/nm1267. ISSN 1078-8956. PMID 16007097.

is a comparative study as opposed to a review article IMO. ​​

• Nicholls, John; Peiris, Malik (2005). "Good ACE, bad ACE do battle in lung injury, SARS". Nature medicine. 11 (8). Springer Science and Business Media LLC: 821–822. doi:10.1038/nm0805-821. ISSN 1078-8956. PMID 16079870.

is a comment rather than a review article either.

• Both ACE inhibitors and angiotensin receptor blockers (ARBs) that are used to treat high blood pressure have been shown to upregulate ACE2 expression hence may affect the severity of coronavirus infections.

is not supported by any reference.

What the systematic review and meta-analysis for human says?

• Caldeira, D.; Alarcao, J.; Vaz-Carneiro, A.; Costa, J. (2012-07-11). "Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis". The BMJ. 345 (jul11 1). BMJ: e4260–e4260. doi:10.1136/bmj.e4260. ISSN 1756-1833. PMC 3394697. PMID 22786934. Use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls (odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I2=79%). The NNT for 2.0 years was 65 (48 to 112). The magnitude of the risk reduction was similar across all study designs (P=0.78 for subgroup differences). Treatment with ACE inhibitors was associated with a significant 27% reduction in risk of pneumonia related mortality compared with controls (0.73, 0.58 to 0.92; I2=51%), without significant differences between estimates from randomised controlled trials and observational studies (P=0.76). In this systematic review we found that treatment with angiotensin converting enzyme (ACE) inhibitors was associated with a significant reduction in risk of pneumonia compared with control treatment and angiotensin receptor blockers (ARBs); the magnitude of this reduction (about one third) was similar across studies with different designs (randomised controlled trials, cohort, and case-control studies). The risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia; it is uncertain if differences exist between ACE inhibitors and ARBs for this outcome.

Taken together, I politely ask folks to review the statements quoted from the body of Angiotensin-converting_enzyme_2 shown above. Thank you!

--Reciprocater (talk) 07:08, 22 March 2020 (UTC)

Concerning both points, the key word is "may". To put the position statement in context, it is important to state why there may be a concern. Inserting the position statement without background makes no sense. Concerning the first point, I have added PMID 18448662 a review article based on mouse experiments (will put this in context shortly). Concerning the second point, I have added PMID 16079870. Boghog (talk) 07:22, 22 March 2020 (UTC)

Thanks for the reply, I attributed it to mice in the article to help distinguish. --Reciprocater (talk) 07:36, 22 March 2020 (UTC)

PMID 27082314 is a WP:MEDRS compliant review documents the possible role of ACE2 and lung damage. Boghog (talk) 07:30, 22 March 2020 (UTC)

Yah there is a theoretical concern. But the concerns is not to such a degree that major medication organizations recommend these medications be stopped. Doc James (talk · contribs · email) 15:55, 22 March 2020 (UTC)

Totally Agree. Just trying to explain why the recommendation was issued in the first place. Boghog (talk) 19:57, 23 March 2020 (UTC)

Italy (finally..) published some epidemiological data [1], English [2]  : "Before admission to hospital 27% resp 16% of the later deceased were taking ACE inhibitors resp. Sartans". Did not see any further analysis of this yet but given the age (avg 78) of the dead and prescription practice in Europe I don't see any dramatic effect upon first glance. Arterial hypertension had a prevalence of some 72% in this population so if anything there is a hint of a protective effect. Some Italian prescription data [3]. Richiez (talk) 18:59, 3 April 2020 (UTC)

Some data from Germany [4] Richiez (talk) 18:36, 4 April 2020 (UTC)

Guang Yang et al, "Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients With Hypertension" [5]

Yingxia Liu et al, "Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients" [6] - of interest this also has some data on beta blockers, thiazides and calcium channel blockers. Although they didn't collect enough patients to get statistically significant data on thiazides, ACEIs, BBs and CCBs there are trends for thiazides (which appear safe or beneficial) and CCBs. Richiez (talk) 20:07, 10 April 2020 (UTC)

• Thank you for the information gathering efforts! Stay safe and healthy!--Reciprocater (Talk) 20:19, 10 April 2020 (UTC)

Are there epitopes on AT-II which are sufficiently similar to epitopes on the covid19 spike protein that antibodies to the spike protein might Cross-React with AT-II?

Does Angiotensin II “AT-II” bind with ACE2 at a site similar to where the Covid spike protein binds?

If so, are there epitopes on AT-II that are antigenically similar to epitopes on the COVID spike protein?

Why might this matter?

Because if so, potentially could

• Antibodies* to the spike protein

Cross React with AT-II, effectively Competing with ACE2 for AT-II (and potentially dysregulating the breakdown of AT-II with widespread downstream physiological/ pathological impact) ?

Any info on this?

Thanks.

G. Holt 2600:1002:B02F:522D:243F:79D8:86DA:7150 (talk) 19:36, 29 November 2021 (UTC)

Above should read “Cross React with AT-II (angiotensin 2)” (not AT-I ... pesky autocorrect!)

Please see previous question 2600:1002:B02F:522D:243F:79D8:86DA:7150 (talk) 19:40, 29 November 2021 (UTC)

Do anti-Spike antibodies cross react with Angiotensin II (AT-II) ?

Possible dysregulation of RAAS? 2600:1002:B02A:E229:A0E8:E61B:27BD:B365 (talk) 21:24, 7 December 2021 (UTC)

Relation with SARS-CoV-2’s viral tropism

According to Oudit et al (2023): SARS-CoV-2’s viral tropism is dependent on ACE2 tissue distribution and expression. I am not sure if this fact is already included in the article, because it is too technical for me. If it is missing, I ask that we include it. Forich (talk) 03:08, 9 March 2023 (UTC)