The role of arachidonic acid metabolism in the pathogenesis of atherosclerosis

Cardiovascular disease, and in particular, the atherosclerotic disorders, are the chief cause of illness, disability and death in many regions of the developed world, where they inflict very high personal, community and health care costs on society. Atherosclerosis, commonly referred to as hardening of the arteries, is an inflammatory disease and is the primary cause of heart attacks, strokes, lower limb loss in diabetics, aneurysms and chronic transplant rejection. Atherosclerosis results in the narrowing of arteries which leads to reduced blood supply, oxygen and nutrients to the affected tissues. Occasionally these plaques can rupture causing a complete blockage of blood supply which can be fatal if it occurs in the heart (eg. heart attack) or brain (eg. stroke). Damage to the inner lining of the blood vessel wall is believed to be the initiating event of this disorder but the mechanism(s) responsible for this injury remain unclear. In the current project, we are interested in how long term use of certain pain relief medications, referred to as anti-inflammatories, contributes to the generation of deleterious oxidative stress which can trigger the onset and progression of atherosclerosis. In recent years there has been much attention given towards this topic as certain pain remedies such as VioxxTM have been pulled off the shelves due to their association with increased cardiovascular events that occur with their chronic use. Based on our previous research, we believe we have identified an oxidative stress pathway that may be induced indirectly as a consequence of the chronic administration of these drugs. We have previously shown that a group of enzymes (CYP2C) can produce reactive oxygen during heart attacks which leads to the abnormal functioning of blood vessels. This dysfunctioning of blood vessels, which is also an early event in atherosclerosis, can be blocked with inhibitors, but it is not known whether CYP2C inhibition prevents atherosclerosis. The current proposal will investigate whether we can prevent atherosclerosis if we inhibit the activation of the CYP2C enzyme. We will also examine whether the administration of certain anti-inflammatories, known to increase cardiovascular events, increase the activity of CYP and reactive oxygen production. Finally, as many people depend on chronic administration of pain relievers such as these, we will investigate the effects of combined administration of CYP2C inhibitors and anti-inflammatory agents towards atherosclerosis pathogenesis. Results from these studies will help us to establish the role CYP2C in atherosclerosis and whether CYP2C inhibitors could be used as pre-emptive treatment for patients identified to be at a high risk for atherosclerotic disease