8 ms·

Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

26 points by Khelavaster 7y ago

anonobviosly 7y ago
That's a quite old (2005) article, dating to the original sars outbreak. https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1 https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1 is a much more recent one, specific to covid-19. (Edit typo)
- rolph 7y ago
  That particular preliminary linked to is too new and requires critical interpretation for a number of issues
  - dnautics 7y ago
    > is too new it's on bioarxiv, what exactly does 'too new' mean?
    - rolph 7y ago
      a preliminary submission has not passed a peer review with the rigor of scientific defense. these sorts of things may be passed among researchers for extended periods of time [years] until all the kinks are worked out of the thesis and a working theory with no known exceptions and independently confirmed agreement of results occurs. jan 26 2020 is the submission date.
      - dnautics 7y ago
        What exactly is the standard of peer review you're expecting? Unless you have reason to think they flat out fabricated the data, the analysis is probably no better or worse than your garden variety nature or science or cell paper.
jfries 7y ago
What are the implications of this?
- rolph 7y ago
  this is the mechanism a coronavirus assembly exploits to enter a cell. the virion uses a peplomer [one of its spikes] to dock with the cell at the ACE2 receptor then wrenches it apart like cutting a door right out of its frame, then the virus inserts itself into the cell leaving its envelope and protien accessories fused with the cell membrane. -if this mechanism can be blocked it will inhibit viral entry -if it can be mimmicked a vaccine is possible here is a good place to start looking at background information: https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_syst... This is what is so damaging to the infected cells to begin with. it disrupts an essential signalling system.
  - epmaybe 7y ago
    Another interesting side effect could be other temporizing measures in the inpatient setting. My understanding from a brief skim of older research papers is that the ACE inhibitors and angiotensin receptor blockers that we use today, like lisinopril or losartan, could upregulate the expression of ACE-2 receptors. If a patient is admitted with coronavirus, discontinuing blood pressure medications such as lisinopril and losartan could be worthwhile to decrease length of stay, morbidity, and mortality.
    - chroem- 7y ago
      I suppose that explains why a lot (most?) of the people who died also suffered from high blood pressure.
      - epmaybe 7y ago
        No, I think that's just the fact that most of the people who died were older with lots of comorbidities, like high blood pressure, diabetes, COPD, etc
pezo1919 7y ago
How can I find it out if I have high ACE2?
- rolph 7y ago
  having high ACE2 is not something that you need to worry about as you only need enough to get the virus in you. - having "high" ACE2 could actually be a benefit if it turns out that you retain proper ACE2 functionality after infection and through the course of the physiological challenge of the virus.
  - seieste 7y ago
    This seems to be in contradiction of other published results. Can you provide a source?
    - rolph 7y ago
      could you please provide citations and the contradictions?
    - ptest1 7y ago
      As far as I can tell, there are no studies showing a higher ACE2 causes more severe disease. Sure, it could, but the pathophysiological models and animal data suggest that it is the loss of ACE2 that may drive disease severity. There is a contradictory preprint (that hasn’t passed peer review) on ACE2 mRNA expression in smokers’ lungs being higher than non-smokers; but there is data saying the opposite happens in animal models of mice exposed to smoke: https://pubmed.ncbi.nlm.nih.gov/20178811-losartan-attenuates-chronic-cigarette-smoke-exposure-induced-pulmonary-arterial-hypertension-in-rats-possible-involvement-of-angiotensin-converting-enzyme-2/ https://pubmed.ncbi.nlm.nih.gov/20178811-losartan-attenuates... There is also an inaccurate preprint on ethnic groups and ACE2 expression with a low n count which also didn’t pass peer review. ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study! Chinese paper discusses this as well: https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-might-be-a-good-choice-for-the-therapy-of-covid-19-pneumonia/?from_single_result=Inhibitors+of+RAS+covid https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m...
m0zg 7y ago
One of the most popular blood pressure medications, Lisinopril, is an ACE inhibitor. A lot of people worldwide (including myself) take it daily. Its mechanism of action is to prevent the conversion of ACE to ACE2.
- unsrsly 7y ago
  Lisinopril is a competitive inhibitor of ACE that prevents it from converting Angiotensin I to Angiotensin II
_bxg1 7y ago
Can we get a (2005)?
- rolph 7y ago
  there is a difference between tech and science with regard to correlations between recency and quality. Scientific articles gain credibility as they age and no known exception to elucidated principles is apparent. in this case the [2005] article is superior to a [2020] article. i do agree however it is helpful and conventional to include a date of publication
  - _bxg1 7y ago
    People reading quickly might mistake it for being about the current Coronavirus. The date would help rule that out.
    - rolph 7y ago
      for all intents and purposes it is about the current coronavirus. regardless of drift the viral peplomer is still being used to dock with the ACE2 receptor protien and still uses a small sequence region to bind the receptor.
CapriciousCptl 7y ago
__This is not medical advice. Do not go out and take a bunch of losartan without a doctor, you could die.__ Here's the article's main point (from 2005): Kuba et al showed that by injecting losartan into mice (a common ACE inhibitor that is off patent) with a SARS-Coronavirus protein leads to less lung injury than the controls without losartan. No studies have shown this works in living, breathing humans, but... (Oral) losartan is widely available (at least right now), it can be prescribed off-label by doctors and picked up today. As its on-label use is treating hypertension, obviously it will lead to low blood pressure, along with all the other possible side effects including life-threatening swelling and more. And since dehydration and sepsis can also lead to lower blood pressure, you'd be playing with fire in life-threatening ways without careful watch by a doctor. You can bet this is a source of ongoing research and trials, probably already underway. __This is not medical advice. Do not go out and take a bunch of losartan without a doctor, you could die.__
- ptest1 7y ago
  This wasn’t in a petri dish actually, this was an in vivo study using mice. Other in vivo studies show similar. There are actually no known trials with ARBs and SARS-CoV-2, which is really weird. There should be. One reason why is because most of the non-crazy (eg Chinese medicine) drugs being trailed were selected by semi-brute force from in vitro type testing. ARBs wouldn’t work in vitro AFAICT, which is a reason they haven’t been tested; the drug won’t stop the virus from entering cells the same way other drugs might, but instead may stop some or all of the major damage the virus does to the body. There’s lots of discussion and papers collected here on this subject: https://twitter.com/__philipn__ https://twitter.com/__philipn__
  - CapriciousCptl 7y ago
    Thanks, corrected my comment. I'd also expect observational studies since ace-inhibitors are so widespread.
- koheripbal 7y ago
  I'm confused. Losartan is a Angiotensin II receptor blocker (ARB). I thought that was different from an ACE inhibitor... https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocke...
noipv4 7y ago
ARB stands for AT1R blockers ( angiotensin II type one ) and they represent a major class of antihypertensive medications. These drugs end in sartan. They will not block ACE2 which is a protein which gets expressed in the lung tissues. Please Do not get carried away. https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2 https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_...
- ptest1 7y ago
  They won’t block ACE2 but as indicated in the article they may prevent the lung damage associated with SARS by blocking AT1R which is the receptor that may mediate lung damage. There’s lots of discussion and papers collected here: https://twitter.com/__philipn__ https://twitter.com/__philipn__
deleted 7y ago
[deleted]

26 points by Khelavaster 7y ago

That's a quite old (2005) article, dating to the original sars outbreak. https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1 https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1 is a much more recent one, specific to covid-19. (Edit typo)

rolph 7y ago
That particular preliminary linked to is too new and requires critical interpretation for a number of issues
- dnautics 7y ago
  > is too new it's on bioarxiv, what exactly does 'too new' mean?
  - rolph 7y ago
    a preliminary submission has not passed a peer review with the rigor of scientific defense. these sorts of things may be passed among researchers for extended periods of time [years] until all the kinks are worked out of the thesis and a working theory with no known exceptions and independently confirmed agreement of results occurs. jan 26 2020 is the submission date.
    - dnautics 7y ago
      What exactly is the standard of peer review you're expecting? Unless you have reason to think they flat out fabricated the data, the analysis is probably no better or worse than your garden variety nature or science or cell paper.

jfries 7y ago

What are the implications of this?

rolph 7y ago
this is the mechanism a coronavirus assembly exploits to enter a cell. the virion uses a peplomer [one of its spikes] to dock with the cell at the ACE2 receptor then wrenches it apart like cutting a door right out of its frame, then the virus inserts itself into the cell leaving its envelope and protien accessories fused with the cell membrane. -if this mechanism can be blocked it will inhibit viral entry -if it can be mimmicked a vaccine is possible here is a good place to start looking at background information: https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_syst... This is what is so damaging to the infected cells to begin with. it disrupts an essential signalling system.
- epmaybe 7y ago
  Another interesting side effect could be other temporizing measures in the inpatient setting. My understanding from a brief skim of older research papers is that the ACE inhibitors and angiotensin receptor blockers that we use today, like lisinopril or losartan, could upregulate the expression of ACE-2 receptors. If a patient is admitted with coronavirus, discontinuing blood pressure medications such as lisinopril and losartan could be worthwhile to decrease length of stay, morbidity, and mortality.
  - chroem- 7y ago
    I suppose that explains why a lot (most?) of the people who died also suffered from high blood pressure.
    - epmaybe 7y ago
      No, I think that's just the fact that most of the people who died were older with lots of comorbidities, like high blood pressure, diabetes, COPD, etc

pezo1919 7y ago

How can I find it out if I have high ACE2?

rolph 7y ago
having high ACE2 is not something that you need to worry about as you only need enough to get the virus in you. - having "high" ACE2 could actually be a benefit if it turns out that you retain proper ACE2 functionality after infection and through the course of the physiological challenge of the virus.
- seieste 7y ago
  This seems to be in contradiction of other published results. Can you provide a source?
  - rolph 7y ago
    could you please provide citations and the contradictions?
  - ptest1 7y ago
    As far as I can tell, there are no studies showing a higher ACE2 causes more severe disease. Sure, it could, but the pathophysiological models and animal data suggest that it is the loss of ACE2 that may drive disease severity. There is a contradictory preprint (that hasn’t passed peer review) on ACE2 mRNA expression in smokers’ lungs being higher than non-smokers; but there is data saying the opposite happens in animal models of mice exposed to smoke: https://pubmed.ncbi.nlm.nih.gov/20178811-losartan-attenuates-chronic-cigarette-smoke-exposure-induced-pulmonary-arterial-hypertension-in-rats-possible-involvement-of-angiotensin-converting-enzyme-2/ https://pubmed.ncbi.nlm.nih.gov/20178811-losartan-attenuates... There is also an inaccurate preprint on ethnic groups and ACE2 expression with a low n count which also didn’t pass peer review. ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study! Chinese paper discusses this as well: https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-might-be-a-good-choice-for-the-therapy-of-covid-19-pneumonia/?from_single_result=Inhibitors+of+RAS+covid https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m...

m0zg 7y ago

One of the most popular blood pressure medications, Lisinopril, is an ACE inhibitor. A lot of people worldwide (including myself) take it daily. Its mechanism of action is to prevent the conversion of ACE to ACE2.

unsrsly 7y ago
Lisinopril is a competitive inhibitor of ACE that prevents it from converting Angiotensin I to Angiotensin II

_bxg1 7y ago

Can we get a (2005)?

rolph 7y ago
there is a difference between tech and science with regard to correlations between recency and quality. Scientific articles gain credibility as they age and no known exception to elucidated principles is apparent. in this case the [2005] article is superior to a [2020] article. i do agree however it is helpful and conventional to include a date of publication
- _bxg1 7y ago
  People reading quickly might mistake it for being about the current Coronavirus. The date would help rule that out.
  - rolph 7y ago
    for all intents and purposes it is about the current coronavirus. regardless of drift the viral peplomer is still being used to dock with the ACE2 receptor protien and still uses a small sequence region to bind the receptor.

CapriciousCptl 7y ago

__This is not medical advice. Do not go out and take a bunch of losartan without a doctor, you could die.__ Here's the article's main point (from 2005): Kuba et al showed that by injecting losartan into mice (a common ACE inhibitor that is off patent) with a SARS-Coronavirus protein leads to less lung injury than the controls without losartan. No studies have shown this works in living, breathing humans, but... (Oral) losartan is widely available (at least right now), it can be prescribed off-label by doctors and picked up today. As its on-label use is treating hypertension, obviously it will lead to low blood pressure, along with all the other possible side effects including life-threatening swelling and more. And since dehydration and sepsis can also lead to lower blood pressure, you'd be playing with fire in life-threatening ways without careful watch by a doctor. You can bet this is a source of ongoing research and trials, probably already underway. __This is not medical advice. Do not go out and take a bunch of losartan without a doctor, you could die.__

ptest1 7y ago
This wasn’t in a petri dish actually, this was an in vivo study using mice. Other in vivo studies show similar. There are actually no known trials with ARBs and SARS-CoV-2, which is really weird. There should be. One reason why is because most of the non-crazy (eg Chinese medicine) drugs being trailed were selected by semi-brute force from in vitro type testing. ARBs wouldn’t work in vitro AFAICT, which is a reason they haven’t been tested; the drug won’t stop the virus from entering cells the same way other drugs might, but instead may stop some or all of the major damage the virus does to the body. There’s lots of discussion and papers collected here on this subject: https://twitter.com/__philipn__ https://twitter.com/__philipn__
- CapriciousCptl 7y ago
  Thanks, corrected my comment. I'd also expect observational studies since ace-inhibitors are so widespread.
koheripbal 7y ago
I'm confused. Losartan is a Angiotensin II receptor blocker (ARB). I thought that was different from an ACE inhibitor... https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocker https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocke...

noipv4 7y ago

ARB stands for AT1R blockers ( angiotensin II type one ) and they represent a major class of antihypertensive medications. These drugs end in sartan. They will not block ACE2 which is a protein which gets expressed in the lung tissues. Please Do not get carried away. https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_2 https://en.wikipedia.org/wiki/Angiotensin-converting_enzyme_...

ptest1 7y ago
They won’t block ACE2 but as indicated in the article they may prevent the lung damage associated with SARS by blocking AT1R which is the receptor that may mediate lung damage. There’s lots of discussion and papers collected here: https://twitter.com/__philipn__ https://twitter.com/__philipn__

deleted 7y ago

[deleted]