The ACE2 Receptor – The Doorway to COVID-19 (ACE Inhibitors & ARBs) (Lecture 37)
Welcome to another MedCram covid-19 update. You can see the numbers here. They are starting to exceed that of mainland China when we look globally. What I want to get to today is something that a lot of you have commented on, and that is the receptor for the SARS-cov-2 virus that causes covid-19.
That is the ACE2 receptor. The ACE2 receptor is how the virus gets into the cell. It’s the doorway and it’s more than just the doorway. Today, we’re going to be talking about exactly what the ACE2 receptor is, and what it’s involved in, and why that matters.
I’ve been wanting to do this for a long time. But the more I looked into it, the more complicated and interesting at the same time that it was. So I want to do the research first and then tell you where we are right now. This has reached ahead because there are a number of people out there that are actually taking different sides on this issue of the receptor. So what it boils down to basically as we’ve talked before outside of the cell, on the surface of the cell, there is a receptor for the SARS-COV-2 virus, which is the thing that causes covid-19, which is the coronavirus.
Here we have the virus, and it’s got these projections that make it look like rays of the sun. That’s why it’s called the coronavirus. This is SARS-COV-2; this is 2019 coronavirus. Here is the S protein that we’ve talked about, and the receptor for this is on the surface of the cell, specifically cells that are found in the lung, the type-2 pneumocytes it’s known as, and also in the GI tract.
This receptor is known as ACE2, and that’s really important for you to understand ACE2. This is where the S protein docks, and then there’s another protein called a serine protease, which is also here in the membrane, which helps to internalize this virus into the cell, and it allows the messenger RNA, which is in here, to come in and infect the cell. The key here though is this protein, that is on the side of the cell, is ACE2, and it’s exactly the same protein that was the receptor for the SARS-cov virus that was back in 2002.
So the question is why is this such a problem? Well, there is some animal data that angiotensin receptor blockers, which is a very common type of high blood pressure medication and ACE inhibitors, which is another common type of blood pressure medication, can increase the concentration of these ACE2 receptors on the surface of the cell.
How do you know if you’re on an ARB or an ACE inhibitor? Typically ARBs end in ‘TAN’, so you might see this as losartan, or irbesartan or candesartan. These are all TANs. They are angiotensin receptor blockers. We’re going to talk more about what they do.
If it’s true that they could increase ACE2 levels, it seems like it will be common sense that if you have more ACE2 receptors on the surface of your cell, now you’ve got more entry points for the virus to infect your cell. ACE inhibitors, they typically end in PRIL, so captopril, enalapril, and the list goes on. Those can also increase potentially your ACE2 receptors.
What do we do with patients who are on ARBs and ACE inhibitors? Well, it seems as though people have higher mortality who have a history of hypertension. So this has led to a number of articles and a lot of social media to talk about “should we get off of our medications that we’re taking for high blood pressure?”
Here is an article that was sent to the Lancet. It was published on March 11th, 2020. The question is “Are patients with hypertension and diabetes mellitus at risk for covid-19 infection?” They talked about the incidence of cardiovascular diseases. They talked about the SARS-COV virus and SARS-cove-2, and the ACE-2 protein which is the receptor for this, and they talked about how ACE inhibitors and ARBs increase ACE expression. The increased expression of ACE2 would facilitate infection with covid-19. They therefore hypothesize that diabetes and hypertension treatment with ACE2 stimulating drugs increases the risk of developing severe and fatal covid-19.
Now, this is only a hypothesis. They say if this hypothesis were to be confirmed, it would lead to a conflict regarding the treatment because ACE2 reduces inflammation. It has been suggested as a potential new therapy for inflammatory lung diseases, cancer, diabetes and hypertension, a further aspect that should be investigated is the genetic predisposition for an increased risk of SARS-cov-2 infection, which might have to do with ACE2 polymorphisms, they say.
Finally, they say they suggest that patients with cardiac disease, hypertension or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe covid-19 infection, and therefore they should be monitored for ACE2 modulating actions such as ACE inhibitors or ARBs. They did not find any evidence to suggest that antihypertensive calcium channel blockers increase ACE2 expression or activity. Therefore these could be suitable alternative treatments in these patients.
Here we have an article, a correspondence to a very major journal, which is raising an alarm on millions of patients who are on these medications and saying that they hypothesize that the patients could be at risk. Obviously, this has raised quite a stir, and the question is “is there any actual truth to this?”
So let’s look and see what the response has been. Here is the response from the European Society of Cardiology. They say because of social media related amplification, these patients taking their high blood pressure medications have become increasingly concerned, and in some cases stopped taking their ACE or ARB medications.
This is what the official response from the European Society for Cardiology: ” the speculation about the safety of ACE inhibitors and ARB treatment in relation to covid-19 does not have a sound scientific basis or evidence to support it. Indeed, there is evidence from studies in animals suggesting that these medications might be rather protective again serious lung complications in patients with covid-19 infection. To date, there is no data in humans.
The Council on Hypertension for the European Society of Cardiology wishes to highlight the lack of any evidence supporting harmful effect of ACE inhibitors and ARB in the context of the pandemic covid-19 outbreak. They strongly recommend that physicians and patients should continue treatment with their usual antihypertensive therapy because there is no clinical or scientific evidence to suggest that treatment with ACE inhibitors or ARBs should be discontinued because of the covid-19 infection.”
So what is it? Which one of these is correct? To delve into the intricacies of that, we’re going to go into some molecular biology. At some point, we’ll get a little complicated, but not too. So bear with me as we go through a detailed instruction on exactly what is going on with the SARS-CoV-2 virus and the renin-angiotensin system.
To understand this, you first start off with a hormone called angiotensinogen, and that is converted into angiotensin I, which will abbreviate AT-1, and that is done through an enzyme called renin that is produced by the kidney. Angiotensin I is then converted into Angiotensin II, and that is done in the lung by an enzyme called ACE.
Now ACE is in the lung; it does convert angiotensin I to Angiotensin II, and we can inhibit ACE by giving someone an ACE inhibitor, and these are the medication that end in PRILs, so captopril and lisinopril, etc.
Angiotensin II is a powerful vasoconstrictor. It also stimulates the adrenal gland to make aldosterone, which has the action of lowering potassium and increasing sodium concentration, therefore increasing blood pressure.
Angiotensin II is a major dividing point because there are two types of states that one can have in the body. So we’ll call this the low state, and we’ll call this the high state. On the cell membrane is a component of proteins that are sitting out on top of the cell membrane, and one of those is ACE2.
When there is not a lot of Angiotensin II around, it is proposed Angiotensin receptor 1 ( ATR1) sits in the catalytic site of ACE2. Now as it turns out, Angiotensin II will be converted by ACE2 into Angiotensin 1, 7. It’s very important for you to understand Angiotensin 1,7 because Angiotensin 1,7 causes vasodilation and decreases inflammation. That’s a good thing.
It’s also possible that you could put and have an Angiotensin receptor blocker that would block this, and that is an ARB. So we’ve talked about Angiotensin receptor blockers, and we’ve talked about ACE inhibitors.
If you have high Angiotensin II, this is the situation that you get. You still have ACE2, but the high levels of Angiotensin II cause the Angiotensin receptor to come off of ACE2. When that happens, when Angiotensin II interacts with Angiotensin receptor 1, the result of that is vasoconstriction, increased blood pressure, increased vascular permeability, pulmonary edema, and presumably ARDS.
Furthermore, when there’s high Angiotensin II, the hypothesis is that this opening in ACE2 allows for the coronavirus with its S protein to bind to ACE2. This binding here also requires something called a serine protease, known as TMPRSS2. Now that can be inhibited with something called camostat mesylate, and that is undergoing trials right now. Interestingly, when you have high levels of AT-II, this entire complex gets degraded into lysosomes.
So let’s review quickly. We’ve got angiotensinogen being converted to Angiotensin I by renin. Angiotensin I is converted to Angiotensin II by an ACE enzyme. ACE inhibitors can prevent that from happening. If you have too much of angiotensin II, then what can happen is that Angiotensin receptor blocker dissociates with ACE2, and it gets activated to cause vasoconstriction, increase blood pressure, permeability, pulmonary edema, and ARDS. That’s exactly what we don’t like to see in these situations in viral pneumonia.
However, if there are low levels of angiotensin II, then what we see is that it gets metabolized by ACE2, and that gets converted into a vasodilator called Angiotensin 1,7. Also, it looks as though ARBs, or Angiotensin receptor blockers, can somehow keep this complex together and keep that catalytic site blocked by the resident ATR Angiotensin receptor, and that can happen with Angiotensin receptor blockers. If angiotensin II is high, however, this dissociation occurs, allowing the virus to potentially bind according to the hypothesis, and that causes degradation.
So what do we see in people who have no ACE? If we take away all of their ACE2, as we’re showing here, what happens? Well, they’ve actually done this in mice. They’re able to breed mice where they delete the gene responsible for making ACE2.
They’re called Knockouts. Double Knockouts mean they take it both on the mother’s side and the father’s side, so when the mouse is born, it has no ACE2 whatsoever. They’ve shown that these mice have a resistance to being infected with the virus because there’s no receptor.
他们被称为敲除。 双敲除（Double Knockouts）意味着他们可以同时在母亲和父亲这边敲除它，因此，当老鼠出生时，它就没有ACE2。他们已经证明这些老鼠对这种病毒没有抵抗力，因为它们没有受体。
But at the same time, what they see in these knockout mice is that they have worse outcomes in viral pneumonia. They have decreased cardiac contractility, and they have increased levels of Angiotensin II, which makes sense because it’s ACE2 which breaks down Angiotensin II when there is a low amount of it.
So these are in what we call ACE2-knockout mice, and these are exactly the things that we’re seeing in patients who are infected with the coronavirus. What they saw in a mouse model of SARS-CoV from 2002 was that there were decreased levels of ACE2 in these viral models, and they had normal ACE levels, but there were less ACE2 levels. They also saw increased levels of Angiotensin II, and when they gave these mouse models ARB, and they gave them ACE inhibitors, this actually improved the outcomes. I’ll show you the links to those studies in the description below.
In a respiratory syncytial virus case, they actually took recombinant ACE2 and gave it to these mouse models, and they found that it improved outcomes. So you can see according to the animal hypothesis, that if you added an ACE inhibitor, it would block this ACE enzyme, making sure that this angiotensin II was on the low side.
But what we may be seeing is that these Angiotensin levels are actually on the high side, and you would predict that if Angiotensin II levels were on the high side, you would expect there would be aldosterone, and low potassium, and high blood pressure. That’s exactly what they saw in very very sick covid-19 patients is that they were hypokalemic, which means low potassium. The most critical of these had higher blood pressure before they crashed.
You can also see here how keeping somebody on an Angiotensin receptor blocker, according to this hypothesis, may improve this kind of a situation, leading to vasodilation and anti-inflammation.
I want to emphasize that while we have good data in mice, when we look at humans, we don’t see these kinds of things happening, at least in the plasma in free-floating ACE. We don’t know what’s going on at the tissue level. So it still may be happening. So the thing I want to stress here is that this is all a hypothesis based on piecing together studies over the last 20 years that they feel that this may be what’s happening. If you’re interested in this kind of research, I’m going to put a bunch of links in the description below that link to the papers that talk about this.
But suffice to say that at this point to go out and say that we should be stopping people on their ACE inhibitors and stopping people on their ARBs, in my humble expert opinion, as much as you want to consider me an expert on this, I would say that the jury is out, and I believe I would come down on the side of the statement from the European Society for Cardiology and saying we really don’t know at this point, and we have some animal studies which actually show that they may be protective in this case.
There’s been a number of reports on the deaths in covid-19 that their ejection fractions, or their cardiac contractility, have been fine when they come in hospital, but over a couple of days of either viral myocarditis, or because of this situation that we’re seeing here that their contractility has dropped significantly as we would expect when ACE2 levels go down.
So this is something that needs to be addressed, and we don’t know exactly what is going to happen until we have those studies. The good news is, according to what I have seen in the last couple of days, there is research looking into starting patients on Angiotensin receptor blockers, or ARBs, so that was a very long explanation over something that has come up very recently.
I think we should continue to delve into this receptor issue, especially when it comes to talking about vaccines because ACE2 is going to play an extremely important role in the future of treatment of covid-19. Thank you for joining us.