In the search for treatments for COVID-19, many researchers are focusing their attention on a specific protein that allows the virus to infect human cells. Called angiotensin-converting enzyme 2, or ACE2 “receptor,” the protein provides the entry point for the coronavirus to latch onto and infect a wide range of human cells. Could this be central in how to treat this disease?
We are expert scientists in pharmacology, molecular biology and biochemistry, with a strong commitment to applying these skills to the discovery of new therapies for human diseases. In particular, all three authors have experience studying angiotensin signaling in various pathological settings, a biochemical pathway that appears to be central in COVID-19. Here are some of the key questions to understand why there is so much focus on this protein.
What is the ACE2 receptor?
ACE2 is a protein on the surface of many cell types. It is an enzyme that generates small proteins – by cutting up the larger protein angiotensinogen – which then regulates the functions of the cell.
Using the spike-shaped protein on its surface, the SARS-CoV-2 virus binds to ACE2 – like a key inserted into a lock – before entering and infecting cells. Therefore, ACE2 acts as a cell gate – a receptor – for the virus that causes COVID-19.
Where is it found in the body?
ACE2 is present in many cell types and tissues, including the lungs, heart, blood vessels, kidneys, liver, and gastrointestinal tract. It is present in epithelial cells, which line certain tissues and create protective barriers.
The exchange of oxygen and carbon dioxide between the lungs and the blood vessels occurs through this epithelial lining in the lungs. ACE2 is present in the epithelium of the nose, mouth and lungs. In the lungs, ACE2 is very abundant on type 2 pneumocytes, an important cell type found in the lung chambers called alveoli, where oxygen is absorbed and carbon dioxide waste products are released.
What is the normal role that ACE2 plays in the body?
ACE2 is a vital part of a biochemical pathway essential for regulating processes such as blood pressure, wound healing and inflammation, called the renin-angiotensin-aldosterone system (RAAS) pathway.
ACE2 helps modulate the many activities of a protein called angiotensin II (ANG II) which increases blood pressure and inflammation, increasing damage to blood vessel walls and various types of tissue damage. ACE2 converts ANG II into other molecules that neutralize the effects of ANG II.
Of greatest relevance to COVID-19, ANG II may increase inflammation and cell death in the alveoli which are essential for bringing oxygen into the body; these harmful effects of ANG II are reduced by ACE2.
When the SARS-CoV-2 virus binds to ACE2, it prevents ACE2 from performing its normal function of regulating ANG II signaling. Thus, ACE2 action is “inhibited”, removing the brakes on ANG II signaling and making more ANG II available to injure tissue. This “decreased braking” likely contributes to injury, particularly to the lungs and heart, in patients with COVID-19.
Does everyone have the same number of ACE2 on their cells?
No. ACE2 is present in all people, but the amount can vary from individual to individual and in different tissues and cells. Some evidence suggests that ACE2 may be higher in patients with hypertension, diabetes, and coronary heart disease. Studies have shown that a lack of ACE2 (in mice) is associated with severe tissue damage in the heart, lungs and other types of tissues.
Does the amount of receptors determine whether someone gets more or less sick?
It’s not clear. The SARS-CoV-2 virus requires ACE2 to infect cells, but the precise relationship between ACE2 levels, viral infectivity, and severity of infection is not well understood.
Even so, besides its ability to bind to the SARS-CoV-2 virus, ACE2 has protective effects against tissue damage, mitigating the pathological effects of ANG II.
When the amount of ACE2 is reduced because the virus occupies the receptor, individuals may be more susceptible to serious illness from COVID-19. Indeed, enough ACE2 is available to facilitate viral entry, but the decrease in available ACE2 contributes to more ANG II-mediated injury. In particular, reduction of ACE2 will increase susceptibility to inflammation, cell death, and organ failure, especially in the heart and lungs.
Which organs are most severely damaged by SARS-CoV-2?
The lungs are the primary site of injury from SARS-CoV-2 infection, which causes COVID-19. The virus reaches the lungs after entering through the nose or mouth.
ANG II causes lung damage. If there is a decrease in ACE2 activity (because the virus binds to it), then ACE2 cannot break down the ANG II protein, which means there is more to cause inflammation and damage in the body.
The virus also affects other tissues that express ACE2, including the heart, where damage and inflammation (myocarditis) can occur. The kidneys, liver and digestive tract can also be damaged. Blood vessels can also be a site of damage.
In a recent research articlewe argued that a key factor that determines the severity of damage in patients with COVID-19 is abnormally high ANG II activity.
What are ACE inhibitors? Are they a possible treatment or prophylaxis of SARS-CoV-2?
Angiotensin converting enzyme (ACE, aka ACE1) is another protein, also found in tissues such as the lungs and heart, where ACE2 is present. Drugs that inhibit the actions of ACE1 are called ACE inhibitors. Examples of these drugs are ramipril, lisinopril and enalapril. These drugs block the actions of ACE1 but not ACE2. ACE1 pilots the production of ANG II. Indeed, ACE1 and ACE2 have a “yin-yang” relationship; ACE1 increases the amount of ANG II, while ACE2 reduces ANG II.
By inhibiting ACE1, ACE inhibitors reduce levels of ANG II and its ability to increase blood pressure and tissue damage. ACE inhibitors are commonly prescribed to patients with hypertension, heart failure, and kidney disease.
Another class of commonly prescribed drugs, angiotensin receptor blockers (ARBs, eg, losartan, valsartan, etc.) have similar effects to ACE inhibitors and may also be useful in the treatment of COVID-19.
Evidence of a protective effect of ACE inhibitors and angiotensin receptor blockers in patients with COVID-19 has been demonstrated in recent work co-authored by one of us – Dr. Loomba.
No evidence exists to suggest the prophylactic use of these drugs; we do not advise readers to take these drugs in the hope that they will prevent COVID-19. We would like to emphasize that patients should only take these medications as instructed by their healthcare provider.
New clinical trial tests ACE inhibitor against SARS-CoV-2
In collaboration with a multidisciplinary group of researchers, Dr. Loomba initiated a multicenter study (randomized, double-blind, placebo-controlled) clinical trial to examine the effectiveness of ramipril – an ACE inhibitor – compared to placebo for reducing mortality, ICU admission, or need for mechanical ventilation in patients with COVID-19.
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