Efffect of antihypertensive drugs on pulmonary ACE2

Angiotensin converting enzyme 2 (ACE2) is a membrane-bound enzyme which enables the coronavirus (SARS-CoV-2) to gain cellular entry and infect cells. ACE2 can be found in the respiratory tract, the nasal mucosa, the eye, the kidneys, intestine and heart. Next to its role in a SARS-CoV-2 infection, ACE2 also has an important physiological function in that it regulates blood pressure as part of the renin-angiotensin-aldosterone system. This dual function of ACE2 plays a central role in COVID-19. On one hand, a reduction in ACE2 density caused by viral infection may aggravate the severity of the disease. On the other hand, certain patients groups with a high density of ACE2 in different tissues may be at higher risk for viral infection. It has been discussed whether treatment with certain antihypertensive drugs may increase the density of ACE2 in the respiratory tract and thereby increase the risk for viral infection. In this project, we will develop a new positron emission tomography (PET) imaging protocol, which will allow us to measure the density of ACE2 in different body tissues after injection of a small amount of a radioactive compound which binds with high affinity to ACE2. This novel imaging protocol will be used to assess the influence of treatment with antihypertensive drugs on ACE2 density in the respiratory tract. Our imaging protocol will help to better understand the role of ACE2 in SARS-CoV-2 infection and will contribute to the development of new drugs to treat COVID-19.

Angiotensin-converting enzyme 2 (ACE2) is a protein found on the surface of many cells in the human body. It acts as the entry point that allows the SARS-CoV-2 coronavirus to infect cells and is therefore the first step in the development of COVID-19. ACE2 is present in the airways, the lining of the nose, the surface of the eye, and in organs such as the kidneys, intestines, and heart. At the same time, ACE2 has an important physiological function: it is part of a system that regulates blood pressure and helps maintain the normal function of several organs. Because of this dual role, ACE2 has become an important target for biomedical research. On the one hand, it enables the coronavirus to enter cells; on the other hand, it is essential for maintaining normal body functions. A better understanding of where ACE2 is found in the body may therefore provide new insights into COVID-19 and other diseases. In this project, we developed a new imaging method that makes it possible to visualize the distribution of ACE2 in the body using positron emission tomography (PET). This method uses a very small amount of a radioactive tracer that binds specifically to ACE2. To create this tracer, the known ACE2 inhibitor MLN-4760 was chemically modified so that it could be labelled with the radioactive isotope fluorine-18. Developing a new chemical synthesis route for this compound was a key achievement of the project. Initial studies in an animal model showed that the newly developed PET tracer, [18F]F-MLN-4760, binds specifically to ACE2 in several organs. The imaging method established in this project provides an important foundation for future research on the role of ACE2 in different diseases. In the long term, it may help researchers better understand disease mechanisms, support the development of new medicines targeting ACE2, and evaluate their effects in living organisms.