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..
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.
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:
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.
- 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?
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:
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
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?
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.
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)
But the research behind what is needed to modulate ACE is already there..