Grant: Operating Grant

Endothelin-1 (ET-1) is a small protein secreted by the endothelium, a cell layer lining all blood vessels and which is in direct contact with circulating blood. In healthy subjects, several mechanisms maintain ET-1 blood levels to a strict minimum. In cardiovascular diseases, on the other hand, the production of ET-1 is enhanced in particular due to the loss of protective 'clearance' mechanisms of the peptide. Albeit ET-1 blockers (antagonists) are prescribed to over 50,000 pulmonary hypertensive patients worldwide, the use of these drugs for the treatment of other diseases such as heart failure, hypertension and atherosclerosis is yet to be conclusive. We wish to investigate, in this proposal, the role of one particular enzyme, chymase, in the production of ET-1 in the cardiovascular system. Chymase, derived from inflammatory mast cells, has previously been reported to produce another constrictor peptide, angiotensin II, within vascular and cardiac muscular walls. Our project hypothesises that chymase may well be involved in the production of ET-1 in the cardiovascular system in whole animals albeit this has yet to be demonstrated. We will therefore assess, in a healthy mouse model, the role of chymase in the synthesis of ET-1. In a second part, we will attempt to circumvent the contribution of the same enzyme in the pathological roles of ET-1 in an atherosclerotic mouse model. We suggest that a better understanding of the enzymes involved in the production of endothelin-1 in physiological and pathological settings may provide important information towards the development of more efficacious antagonists for the treatment of atherosclerosis and other cardiovascular dysfunctions.