The Role of ACE2 and Treatment Implications for COVID-19

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The topic of this article was inspired by a series of concerns circulating via social media about the impact of certain blood pressure medications, as well as thiazolidinediones (prescribed for some diabetic patients), and NSAIDs (ibuprofen, naproxen, aspirin, etc.) on the outcome of patients suffering from COVID-19 caused by the 2019 coronavirus. 

Before you skim this article and come to a quick conclusion to stop these medications, please slow down and understand that there are two sides to this story.

To illustrate this debate clearly, we are going to have to take a closer look at the molecular biology that scientists are studying as they seek medical solutions to this pandemic.

The story of how the SARS-CoV-2 virus infects the human cell starts with a special receptor on our cell membranes – notably found on Type 2 pneumocytes of the lung, as well as cells in the GI tract. This receptor is called Angiotensin Converting Enzyme-II, or ACE2. This is the same receptor used by the 2002 SARS-CoV virus, which has been studied extensively. [See figure 1]

The “S protein” of the virus binds to the ACE2 receptor which then acts as a gateway for the virus to gain access to the interior of the cell. With the help of another membrane protein called serine protease, the virus is able to dump its RNA into the cell, where it uses human cellular apparatus to replicate. Replication of the viral RNA allows the disease to spread and infect the host.

Why is this an issue? Scientists are taking different viewpoints on what this means. 

A recent paper published in the Lancet hypothesized that ACE inhibitors (for example, Lisinopril) and angiotensin receptor blockers (ARBs: for example, Losartan) increase ACE2 receptors and so provide more sites for viral binding. Because patients with hypertension are showing a higher mortality risk, authors of the paper suggest that these medications may possibly be correlated with heightened disease states in patients who take them. 

If you are among the millions of patients who are on one of these, and you worry that you should stop your meds, please KEEP READING!

There is more to the story, and as we have seen before, the biology is more complex than at first glance. 

The Council on Hypertension of the European Society of Cardiology disagrees with the Lancet article, claiming that we have no clinical or scientific evidence, and that theoretically the opposite may be true. They state that these medications may be protective during disease states. 

Let’s take a closer look at some of the biology around blood pressure regulation to understand why. 

First, let’s identify the key players in the game of blood pressure balance:

  1. Angiotensinogen is produced mainly by the liver. Angiotensinogen is a precursor to Angiotensin-1 (AT-1).
  2. Angiotensin-1 (AT-1) is produced in the kidneys when the hormone Renin acts on player 1, Angiotensinogen.
  3. Angiotensin-2 (AT-2) is produced in the lungs by an enzyme called Angiotensin Converting Enzyme (ACE). AT-2 is a vasoconstrictor, and raises blood pressure.
  4. Angiotensin Converting Enzyme (ACE) is an enzyme produced in the lungs and converts AT-1 to AT-2, ultimately setting into motion a cascade of events that signals the kidneys to dump potassium, retain salt, and raise blood pressure. ACE inhibitors are a class of drugs that block ACE and so lower blood pressure.
  5. ACE2 is a protein found on the cell membrane, notably in lung and gut tissue. When AT-2 is low, ACE2 is bound by Angiotensin Receptor-1 (ATR-1) and AT-2 is converted by ACE2 into a vasodilating, anti-inflammatory, blood pressure lowering compound called Angiotensin 1,7 (AT-1,7). All a good thing! ARBs (Angiotensin Receptor Blockers) are a class of drugs that keep the ACE2/ATR-1 complex together, blocking the ability of AT-2 to bind with ART-1, lowering both blood pressure and inflammation.
  6. Angiotensin Receptor-1 (ATR-1) binds to, and activates AT-2, promoting a rise in blood pressure. If AT-2 levels are low, ATR-1 binds with ACE2, and blood pressure drops.

So we have two scenarios:

 

 

The first happens when AT-2 levels are low. This can happen naturally, or as a result of taking an ACE inhibitor. In this scenario, ATR-1 binds with ACE2 and AT-2 will not be activated to raise blood pressure. ACE2 will convert remaining levels of AT-2 into the blood pressure lowering and anti-inflammatory molecule AT-1,7. 

Now here comes the interesting part: Theoretically, when the ACE2 is bound by ATR-1, the ACE2 receptor is no longer available to the virus. 

This means the virus will have no entry to the cell, and replication will fail

The second scenario happens when AT-2 levels are elevated. This happens when the kidneys detect low arterial blood pressure and sodium. Elevated AT-2 stimulates the adrenals to release aldosterone, which then dumps potassium into the urine, and retains sodium, causing blood volume and then blood pressure to rise. Furthermore, AT-2 is a powerful vasoconstrictor so it also raises blood pressure.

 

Now here comes the second interesting part: When AT-2 levels are elevated, the ATR-1/ACE2 complex splits, liberating ACE2 and exposing it, potentially to the S-protein of the coronavirus.

Meanwhile, the free ATR-1 binds with AT-2, activating vasoconstriction, increased vascular permeability, pulmonary edema, and hypothetically Acute Respiratory Distress Syndrome (ARDS). 

If AT-2 levels remain elevated, aldosterone is also elevated, potassium levels drop (hypokalemia), and blood pressure rises. If this is how patients with serious and life-threatening symptoms present, then, hypothetically, ACE inhibitors or ARBs may help prevent this. This is ALL hypothetical.

In ACE2 gene-deleted mice, resistance to the virus was demonstrated, but they also showed worsened outcomes in viral pneumonia, as well as decreased cardiac contractility and increased levels of AT-2. This animal study has not correlated with human plasma studies, although it still may be occurring at the tissue level. 

Mouse models of 2002 SARS-CoV viral infections demonstrated that ACE Inhibitors and ARBs actually improved outcomes. 

The final conclusion?

We don’t really know yet. However, it makes sense to use caution before stopping these medications. Research is actively looking into the possibility of using ACE inhibitors and ARBs to improve outcomes during the disease progression. This could have a significant impact on our treatment protocols for COVID-19.

Further reading:

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