Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005) | Hacker News Reader

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

nature.com

26 pointsKhelavaster55 comments

__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.__

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__

Thanks, corrected my comment. I'd also expect observational studies since ace-inhibitors are so widespread.

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_blocke...

they would both have the effect of altering the state of the renin-angiotensin system

they work from different ends:

the receptor blocker, inhibits angiotensin II from binding

the ACE inhibitor, interferes with conversion of angiotensin I > angiotensin II ,,,,thus reducing the interaction between angiotensinII and the receptor.

In the case of ACE inhibitor the receptor is open and available for docking,,,in the case of the blocker, there is something that _may_ get in the way of viral peplomer docking to the receptor

ideally there exists, some sort of receptor blocker that competetively inhibits coronavirus peplomer binding but is also displaced by angiotensin II ,,, or binds in a site that does not interfere with the ligand recognition sites but prevents the binding of peplomer

Just a little clarification. These renin-angiotensin terms are totally confusing (due to how similar they all are!) and from my correspondence with physicians, many of them even get them mixed up!

Virus binds to and downregulates ACE2. ACE2 converts Ang II to Ang 1-7. Ang II binds to AT1R and AT2R receptors:

https://twitter.com/__philipn__/status/1229607854232850432?s...

Pic for clarity.

When there’s less ACE2, and in general due to immune response, there will be more Ang II to bind to AT1R. This AT1R binding may create the lung injury seen with the virus.

The idea is that by blocking AT1R with an ARB type drug you don’t stop the virus from entering a cell, but you instead stop the body’s pathological response to the virus. After all, most viruses don’t kill us, and our immune system - if it doesn’t over react - will usually kill a thing if it has enough time and the virus isn’t “special” like HIV or herpes (that’s my general, non expert understanding!)

While it seems smart to try and inhibit ACE2 directly, there are a couple problems with this I see:

1. It may be pathological. More Ang II to bind to AT1R, you might end up way worse off. ACE2 is the “good” ACE, and all the evidence we have seems to suggest that a reduction in the ACE2:ACE ratio will make tissue fibrosis, death, etc worse. This happens in the heart and lungs in mouse models.

2. Small molecule ACE2 inhibitors bind to the C shaped area of the ACE2 enzyme, while the virus attaches to the back. So they likely may not inhibit cell entry:

https://twitter.com/robertlkruse/status/1230577662751641601?...

The best silver bullet bet here is ACE2-fc, which isn’t a small molecule.

This is a soluble form of the ACE2 protein along with an fc. this gives it a longer half life in the body.

This would likely:

1. Stop virus cell entry by neutralizing the virus- virus binds to ACE2-fc instead of the cell ACE2.

2. Stop potential lung damage from AT1R activation.

Both 1 and 2 have been shown in some models.

It is now being tested in vitro. Next animals.

Chinese are testing non-fc form, ACE2 directly, but requires IV drip. Testing now directly in humans! 7 day trial.

See twitter for more on this:

https://twitter.com/__philipn__

If you’re a funder, VC and you’re reading this: The scientist at John Hopkins who’s developing ACE2-fc is looking for funding. He’s working with Chinese biotech firms now to do the testing. Please comment here and I will connect you.

So, to be clear, a patient should stop taking Losartan if he suspects he has covid-19, correct?

you should stop taking losartan if directed to do so by your doctor.

this thread is descended from a conversation about recent discoveries and lead considerations that are not yet perfected and very probably not completely understood.

I get the idea that its tempting to try and find a physiological sweet spot where you can evade the virus,

but virus has a number of tools that work in concert to manipulate the host physiology into a working environment and exploit molecular machinery.

this ACE2 related pathology is likely multiprong so disruption of one aspect will not be sure to reduce harm.

on the flipside blood pressure modulators can be a problem with incorrect dosage. Your doctor has a better scoop on your health status then i could have in any short time so thats where you should ask about changing dosage, and getting some idea of just how much risk you might have if your exposed to the virus.

Although I suspect someone who's already taking Losartan and has a blood pressure increase due to covid19, a small increase in Losartan dosage is likely a low-risk effort that looks like it might be beneficial.

increase Losartan dosage? beneficial? Highly unlikely.

Ok, so then (assuming this all gets verified), then the recommendation for covid-19 patients taking Losartan, is that they stop taking it, correct?

the TL:DR is dont stop your meds unless your doctor says so.

The gist of the thesis so far:

here is what we think is known so far.

ACE2 adjusts the amount of angiotensin II [given]

and when angiotensin II docks to its receptor [AT2] this results in a signal to increase your blood pressure.

this receptor [AT2] is where losartan does its job, it inhibits binding of angiotensin II to the AT2.

what the virus seems to do is dock with and disrupt the ACE2 protien, so your ability to adjust howmuch angiotensin II is free and available is disrupted.

what does this do? there is a lot more angiotensin II encountering the AT2 receptor, this causes blood pressure to go up, this causes the lungs to generate fibres between cells, this causes lung tissue to become less than optimum at being pliable elastic and permeable to gases.

This is not a good time to have a blood pressure spike. this is probably not a good time to do anything that increases the angiotensin II signal to the AT2 receptor.

your losartan _may_ actually help you.

now keep in mind this is ongoing way out to the very edge, preliminary research so dont do something risky like screwing around with these meds when this isnt even finished science.

Ok, I see - so the ultimate recommendation may actually be to increase someone's losartan dosage.

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

(Edit typo)

That particular preliminary linked to is too new and requires critical interpretation for a number of issues

> is too new

it's on bioarxiv, what exactly does 'too new' mean?

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.

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.

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_...

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__

What are the implications of this?

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_syst...

This is what is so damaging to the infected cells to begin with. it disrupts an essential signalling system.

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.

I suppose that explains why a lot (most?) of the people who died also suffered from high blood pressure.

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

it doesnt explain it, but it is something worth chasing to its end for a possible therapeutic benefit.

its does suggest that such comorbidities such as high blood pressure or existing lung disorder disease or other wellness impairment ---

--- could contribute to mortality

this is something of a bush to beat around.

- when the virus docks with the ACE2 receptor there is a loss of the ACE2 receptor function as it is a destructive process.

- when the virus inhabits the cell there is probably a cytoplasmic down regulation of ACE2 expression as the cell is now "claimed" as a place for replication

so the question would be when would we administer or withdraw such an ACE2 blocker

the loss of ACE2 functionality is devastating to the cell but the presence of functional ACE2 receptor makes a cell vulnerable to entry

-and should we be using a blocker pe se or should we use some sort of hypothetical receptor inhibitor that is not displace by coronavirus spike protien, as in competetive inhibition?

I wrote a long comment and it got deleted, argh!

Best guess? ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity:

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-m...

They reason that 1) ARB doesn’t increase ACE2 past normal human baseline anyway, just to normal status 2) Younger have higher ACE2, older women more than older men; both groups more protected so disease severity unlikely from higher ACE2.

ACE2-fc being developed- will both stop AT1R activation and neutralize virus:

https://twitter.com/robertlkruse/status/1233986542097567744?...

He is looking for funding if any funders are reading this. Comment here and I can connect.

there would be an upper concentration of ACE2 receptor per unit of cell membrane that would elicit increased probability of receptor and viral peplomer interaction. once that concentration is reached, further increase of the docking probability would not occur.

there is a dynamic here as the virus, in sufficient titre encounters the receptor, binds enters the cell and typically disrupts normal translatory events in the cytoplasm.

the effect is to exclude further infection of the cell with increased copy number of virions, thus replication occurs instead of immediate cell apoptosis

I guess what I think could be possible is:

ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https://twitter.com/__philipn__/status/1233569567512772609?s... but this may be beside the point.

Other coronaviruses that use more common receptors are not as lethal. Even if the virus has a higher probability of cell entry, does that make it more lethal?

Check out this paper:

https://twitter.com/__philipn__/status/1229568317167243264?s...

Proportion of reduction of ACE2 correlates with disease severity.

Check out figure 1

“Differences in clinical outcomes did not correlate with differences in viral replication efficiencies.”

Compare C and D. Viral replication basically the same between young and old mice. But old had severe disease.

So I’m not sure it’s as simple as increased replication (a proxy for cell entry?) that drives severity.

Edit: just re read your final sentence. Great point. But in the case of ARB usage, while ACE2 may be upregulated and the cell may have another ACE2 cleaved by the virus, if AT1R blockade was occurring then maybe the lung damage would not happen.

Is the cell itself worse off with more than one copy of the virus inside of it? Or would the damage be the increased loss of ACE2?

If damage from increased loss, then I can see the ARB approach helping.

If more than one copy of virus in cell is really bad, then sounds like this could be more complicated. But I do wonder about other viruses which have lots of receptors available, and why this one is so serious in some, but not most, people.

the physiological cascade that occurs due to disruption of a homeostatic feedback system is the most probable cause of direct lethality. The setpoint and the relative concentrations of the elements in these systems are genetically dictated functions.

There is probably some correlate between predisposition to morbidity/mortality and how far ones setpoints deviate from population setpoints.

there are 2 prongs to this attack, one is the disruption of angiotensin based signalling and effectation

the other is the viral entry to the cell. the virus must do a dance on the head of a pin in a sense to replicate but not hijack somuch of the cells basic metabolism that apoptosis occurs. a virus that allows its host cell to remain viable wins the lottery for natural selection.

the problem is that the virus occupies the expression machinery that creates ACE2, in an indiscriminant fashion many other protiens as well.

so this means the virus has caused damage by entry

the entry damage causes errent feedback which causes further physiological perturberance

a secondary round of disruption occurs when ACE2 expression is inhibited thus interfereing with replenishment of ACE2 that has been damaged as well as disrupting the regular recycling of ACE2 and for that matter disrupts expression of the ATI and ATII receptors

---I am not a founder or funder but simply a concerned professional

Can you please give me a pointer on these researches?

Also its not clear to me: do blood pressure mediacations in general upregulate the expression of ACE-2, or is it possible that they downregulate it? (Not lisonopril or losartan)

you can do both depending on the med and there are different mechanisms of action.

Also :

any sort of EXPERIMENTATION should be done in a clinical setting with qualified professionals,

this discussion is about scientific research and is not even close to being acceptable for clinical trials.

blood pressure medication is normally prescribed with physician monitoring the patient for desirable or undesirable effect

Lisinopril and losartan are usually stopped in patients admitted to the hospital for an infection.

Sorry I don't know much about the topic.

How can I find out if I have too high (?) ACE2, and what can I do about it? Are there sympthoms at least?

look here:

https://news.ycombinator.com/item?id=22458302

the meds modulating ACE family of proteins are also commonly available as blood pressure meds, actually. But interestingly, the side effect is...coughing...

But the research behind what is needed to modulate ACE is already there..

Sorry I don't know much about the topic.

0. How can I find out if I have too high (?) ACE2, and what can I do about it? Are there symthoms at least?

1. What does modulating ACE means? 2. Do you mean shall everyone get those blood pressure meds? Or what is the relation now with these meds in terms of action? Does it mean people who need it must get it for sure? 3. Research what is needed to modulate ACE: can you please give a pointer.

have a look here ;

https://news.ycombinator.com/item?id=22458302

Thanks a lot

Does modulation mean increasing or decreasing ACE2? I assume it decreases and its good, right?

modulation means in this case means dynamically increase or decrease in order to stay on a curve

Thanks

Anecdotal, but as someone who takes Losartan daily, it does not make me cough at all...

It did make my prostate feel swollen for a couple days though.

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.

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

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

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.

This seems to be in contradiction of other published results. Can you provide a source?

could you please provide citations and the contradictions?

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...

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...

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-m...

Can we get a (2005)?

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

People reading quickly might mistake it for being about the current Coronavirus. The date would help rule that out.

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.

Reply on news.ycombinator.com