Harnessing natural heart-protective molecules to prevent heart disease

Activation of soluble Epoxide Hydrolase by intra-protein disulfide formation - role in regulating cardiovascular function in health and disease

Epoxyeicosatrienoic acids (known as EETs) are naturally occurring molecules that play a protective role against heart and circulatory diseases, by reducing blood pressure, inflammation and atherosclerosis. However, EETs are broken down by an enzyme called soluble epoxide hydrolase, or she, which removes these protective effects. Dr Rebecca Charles, at King’s College London, is studying how sEH is controlled. She has identified two new ways in which this occurs, and has shown that these two ways are linked together. In the first, naturally occurring fat molecules attach to part of the enzyme and act as ‘nature’s own’ inhibitors by blocking its action. In the second, a chemical change happens to the enzyme , changing its shape and making it easier for the enzyme to grab onto EETs, ramping up its actions in breaking them down. However, this change in shape also allows greater access to the natural fat molecules that block sEH activity. By developing a drug that can cause this change in shape, Dr Charles believes sEH could be made more sensitive to these natural inhibitors, shifting the balance to allow protective EETs to remain active. With this BHF Intermediate Basic Science Research Fellowship she will develop a lab model with the altered sEH enzyme, and use this to study effects on heart health and disease, while searching for potential drugs that cause this change to occur.