What regulates steroid hormone release in tissues? Identifying new mechanisms and therapies for cardiovascular risk

Tissue specific determinants of glucocorticoid signalling in humans- new mechanisms and therapies for cardiovascular risk- renewal

Chest pain and heart attacks occur when heart muscle is starved of oxygen as a result of coronary heart disease. The condition develops when arteries to the heart become narrow because of fatty build-up in the artery walls. Many factors increase our risk of developing heart disease. Professor Brian Walker’s research at the University of Edinburgh’s BHF Centre of Research Excellence has demonstrated that certain hormones increase the risk of developing cardiovascular disease. He has shown that high levels of the stress hormone cortisol are associated with obesity, high blood pressure and type 2 diabetes. He has identified a link between certain genetic changes and variations in blood cortisol levels and advanced our understanding of the mechanisms linking obesity with heart disease risk. Professor Walker’s team has also identified an enzyme - 11ß-HSD1 – that generates cortisol in fat tissue and liver. Inhibitors of this enzyme are currently being explored in Phase II trials as a potential new therapy for controlling cortisol release and reducing the risk of heart disease. In addition to the enzyme 11ß-HSD1, the team has found that other factors also control cortisol levels in the bloodstream, and tissue sensitivity to cortisol. Cell surface sensors called mineralocorticoid receptors (MR) and hormone transport within cells also play a role. The new award will allow the team to explore the relative contributions of these factors in cortisol sensitivity. The team will also use samples and data from approximately 20,000 people (the CORNET consortium) to work out how genetic variants in sensors such as MR influence cortisol levels and the consequences for cardiovascular risk. The results of this programme will provide new insights into cortisol and may identify new targets for therapies that will protect against heart disease.