What is ACE2?

14 May 2020

Interview with 

Josef Penninger, University of British Columbia; Patricia Gallagher, Wake Forest School of Medicine

BLOOD_CELLS

Artist's impression of red blood cells

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There's a system of hormones in our bodies that controls blood pressure called the renin-angiotensin system. The crucial parts, for this story, are: a hormone called angiotensin; and some enzymes that convert it, aka angiotensin converting enzymes - A C E. This is what ACE2 stands for. One of the people who first discovered much of this is Austrian researcher Josef Penninger, and he explained it to Phil Sansom...

Josef - Because the system called the renin-angiotensin system and this system, for instance, regulates blood pressure, it regulates our heart functions, our kidneys. It's one of the most fundamental systems for our basic physiology and there are two enzymes which regulate this: ACE and ACE2. ACE constricting blood vessels, and ACE2 the opposite - it opens the blood vessels and keeps us healthy, keeps multiple of our organs healthy.

Phil - Can you help me picture what it kind of looks like?

Josef - Yes, so the ACE2 basically is produced inside the cells and then it goes to the surface of the cells. Part of it is still in the cell. The business end is outside of the cell. It sits on many, many tissues because the system has multiple functions in our body.

Phil - Why do viruses come into all this?

Josef - So the viruses came into this because after we had found it, then we found a totally novel system that ACE2 actually protects against lung failure. At this time when we start working on this, basically built an ICU for mice, which took us years to do.

Phil - Did you consider calling it a mice-CU?

Josef - That's a great idea. Mice-CU it actually is! So we built a mice-CU and found to our surprise that ACE2, like in the heart, is this good guy. Without ACE2 blood vessels started to leak, the whole lung became a full of water, full of inflammation. And then a group in Boston said that ACE2 could be a candidate receptor for the first SARS virus. That basically clicked because if ACE2 protects from lung injury and the SARS virus causes a very severe lung disease, maybe the two fit together.

Phil - What exactly is the relationship between these viruses and the ACE2? Is the ACE2 the thing the viruses are attacking?

Josef - ACE2 is the door into our body for the viruses. The virus can only live if it enters our cells in our body, and to enter the cells in our body it needs a gate. ACE2 is the central entry gate for the first and now the second SARS coronavirus.

Phil - Are you saying that this is the reason that these coronaviruses do the damage that they do because they're using this ACE2 which ordinarily would help against lung infection?

Josef - Correct. It's a really evil, you know, there's no moral for viruses, but it's a real evil virus to hit one of our essential protective systems.

Phil - And when they hit that gate, do they also sort of use it up?

Josef - Exactly. So they don't just open it, they actually take the gate with them inside the house. And that's why believe these two particular viruses became so dangerous.

Phil - So you're saying there's kind of this double whammy of both the damage inside the cell and the damage you get from losing this helpful ACE2, which is sort of why this current virus has been such a problem.

Josef - Correct. This double whammy. And because the gate doubles as a good guy in our body.

Phil - You mentioned that ACE2 does all this stuff to stop you getting, for example, high blood pressure. If the coronavirus is getting rid of that, are we seeing patients with the coronavirus who've got, you know, blood pressure issues or something like that?

Josef - Yeah. What's really interesting is, you know, if you look at the cases, people who died unfortunately of Covid-19, most of them have actually had a disease before. And the diseases they have before are diabetes, which affects the blood vessels, cardiovascular diseases, hypertension, exactly where ACE2 has actually a critical role. It's very suggestive. And now it turns out in the latest stage of Covid-19, there's this rampant infection of more or less old blood vessels. So it does explain a lot.

ACE2 is the doorway that the virus uses to get into our cells. But not everyone’s cells have the same number of doors, so to speak. To find out more, Phil got in touch with another biologist who’s long researched ACE2...

Patricia - I'm Patricia Gallagher, I'm a Professor in the Hypertension Research Center at Wake Forest University in Winston Salem, North Carolina.

Phil - And I have to say you're sounding pretty good right now. Where in your house are you?

Patricia - I'm in a closet. You have put me in the closet.

Phil - I feel bad when you put it like that.

Patricia - That's all right.

Phil - So tell me about ACE2.

Patricia - One of the primary functions of ACE2 is to maintain the proper balance between two hormones: angiotensin 2, and angiotensin 1-7. Now these two hormones are coursing through your body as we speak, angiotensin 2 constricts or narrows blood vessels while angiotensin 1-7 dilates or opens blood vessels up.

Phil - That's kind of a funky naming system. Why isn't it angiotensin 2 and angiotensin 3?

Patricia - Well, angiotensin two is eight amino acids long, and ACE2 cleaves one of those amino acids to produce angiotensin 1-7. Angiotensin 2 also promotes inflammation. While angiotensin 1-7 has anti-inflammatory properties. ACE2 ensures that the levels of these two hormones are balanced, so there's proper defense against invaders and so that your blood pressure is not too high or too low, so it's kind of a ying and yang thing.

Phil - How important is it in the grand scheme of your body?

Patricia - Well, we think of ACE2 and angiotensin 1-7 as part of a pathway that protects against chronic diseases such as hypertension, heart failure, cardiovascular and lung disease, and diabetes. SARS and Covid have hijacked this essential protein as their host receptor and in the process wreaked havoc in the patient.

Phil - Does that mean then that if you reduce the amount of this ACE2 that you have that might protect you against the coronavirus?

Patricia - Well, it's a complicated issue. Before, or in the initial stages of infection, that might be a good thing. But later on when you've got that severe pneumonia, high levels of systemic inflammation, increasing ACE2 may be a good idea.

Phil - So you're saying that even though it's what the virus uses to get into you, it's still useful to have when you've got the virus because it does all these good things?

Patricia - In the later stages definitely, I would think high levels of ACE2 may be a good thing and there are actually clinical trials right now looking at drugs that cause an increase in ACE2 to give to patients in the latter stages of disease.

Phil - Now do different people naturally have different amounts of ACE2 to start with?

Patricia - There's a lot of data accumulating now on a few levels. There are studies showing that Asians, particularly Asian females, have high levels of ACE2 compared to other ethnicities. Men have higher levels of ACE2 than women. ACE2 also increases as we age. This increase in ACE2 with age may in part explain why Covid-19 has such devastating effects in patients over 60, but also these patients tend to have chronic disease. This is a complicated process.

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