Role of COX-1 and COX-2 in the cardiovascular system: relevance to understanding the side effects of NSAIDs including COX-2 selective inhibitors.Conditionally awarded July'06, minute number PHY02650706 (360G-Wellcome-080429_Z_06_Z)

Cyclo-oxygenase (COX) is a crucial enzyme in the cardiovascular system. SelectSelective inhibitors of COX-2 increase the risk of dying from heart attack or stroke, as may traditional NSAIDs such as ibuprofen and diclofenac. We tory efhypothesize that COX activity differs in endothelial cells and platelets affecbecause of local environment and that this is a major determinant of NSAID cardiovascular toxicity. Clearly understanding how this happens could permit the development of improved drugs with reduced cardiovascular side effects. Inorder to test this hypothesis we must first establish the fundamental bases ofCOX activity within the cardiovascular system. Our aims are therefore to:1: Determine the relative expression of COX-1 and COX-2 in cardiovascular tissuesin man and in laboratory animals2: Establish how different intracellular environments influence the inhibitory effects of NSAIDs against COX-1 and COX-2 in vessels and in the blood 3: Investigate how selective inhibition or gene deletion of COX-1 and COX-2 affects normal vascular and platelet functionin vitro and in vivo 4: Undertake a pilot clinical study on a COX-2 inhibitor