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ACE2 and the health of major organs

The cause of COVID-19 is a virus called SARS-CoV-2. This virus uses a receptor on the surface of cells in order to gain entry to and infect cells. The receptor is called ACE2. Once inside a target cell, SARS-CoV-2 engages with enzymes in the cell to cause infection.

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Distribution of ACE2

In 2003-04, scientists were trying to understand how a related virus, SARS-CoV (the cause of severe acute respiratory syndrome), was able to enter cells. They found that SARS-CoV also used ACE2.

ACE2 is found on many different types of cells in different parts of the body, including the following, which we have grouped together as they have a related function:

  • mouth, nose, throat and lungs
  • stomach and intestinal tissues, including the colon
  • bone marrow, lymph nodes, spleen and thymus gland
  • liver
  • brain
  • cells lining the arteries, the heart
  • testicles

Although ACE2 is found on the surface of many cells in the body, research has found especially high levels of ACE2 on tissues from the cardiovascular system, intestines and kidneys. These high levels of ACE2 may, in theory, make these tissues more susceptible to infection and injury from SARS-CoV-2.

In sickness and in health

The normal role of ACE2 is to help break down a hormone called angiotensin II to angiotensin. This conversion of angiotensin II helps to reduce tightening of blood vessels and signals the kidneys to remove sodium from the blood, helping to reduce blood pressure. Thus, ACE2 has a protective effect on the cardiovascular system and kidneys. ACE2 also has other protective roles, such as anti-inflammatory effects and likely reducing the risk of excessive formation of blood clots.

Back to the virus

Once SARS-CoV-2 infects a cell, it is somehow able to get the cell to reduce expression of ACE2 on its surface. If many cells in an organ-system are infected and reduce their expression of ACE2 on their surface, the result is that there are insufficient levels of ACE2 to protect cells from inflammation-related injury.

In the case of SARS-CoV-2-infected lung tissue, scientists think that the subsequent loss of ACE2 expression could increase the risk of lung injury arising from infection by this virus and/or bacteria.

The heart and blood vessels

SARS-CoV-2 can infect the heart and cells lining blood vessels. People with severe symptoms of COVID-19 have elevated levels of proteins in the blood, suggestive of heart injury (we will have more details about these proteins in another article in this issue of TreatmentUpdate). It is at least plausible that the loss of ACE2 arising from SARS-CoV-2 infection of the heart and blood vessels could contribute to cardiac injury—abnormal heart rhythms, heart failure and other issues—that has been reported in some people with severe symptoms of COVID-19. Doctors have found that people with underlying cardiovascular injury seem to be at elevated risk for severe COVID-19 associated problems.

Theories about ACE2

There are several theories about ACE2 and its role in COVID-19. These theories are largely based on data collected from past experiments with cells and with animals and have not been done in the context of the current pandemic.

Genes

Not everyone has the same level of ACE2 expression in their body. Scientists have found that there are differences in populations concerning ACE2 expression and the risk for cardiovascular disease. This risk may be related to differences in genetic makeup between groups of people. This difference in expression of ACE2, related to genes, may be one reason why some people are more susceptible to COVID-related injury of organs.

Gender

Women have two X chromosomes (written as XX) and men have one X and one Y chromosome (written as XY). The ACE2 gene is associated with the X chromosome. Since the cells of women have two copies of this chromosome, they may have higher levels of ACE2 than men. This difference may, in part, explain some reports that men seem to be significantly more affected by severe COVID-19 than women. However, this idea needs further exploration in well-designed analyses.

Blood pressure treatment

Many medicines for treating higher-than-normal blood pressure and cardiovascular disease raise levels of ACE2 on the surface of cells. In theory, this could provide more opportunities for SARS-CoV-2 to infect such cells. However, the consensus among leading cardiovascular and kidney specialists and their professional societies is that the benefit of these drugs on a person’s overall health outweighs any theoretical concerns about enhancement of SARS-CoV-2 infection.

Well-designed clinical trials will be needed to explore the issue of blood pressure medicines and COVID-19. Examples of such trials that are planned or underway include the following:

  • a medicine called losartan that has been used to treat hypertension
  • intravenous infusions of ACE2

—Sean R. Hosein

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