Atherosclerosis is an inflammatory disease characterized by the build-up of cholesterol-laden plaque in artery walls. Progression of atherosclerosis results in injury to the structural integrity of a vessel and may ultimately lead to thrombosis, stroke and myocardial infarction. During the pathogenesis of atherosclerosis, alterations in prostaglandin biosynthesis occur by mechanisms that are not well understood. Prostaglandins are a group of biologically active compounds derived from the cyclooxygenase (COX) catalytic pathway and comprise the commonly named prostaglandins as well as thromboxanes and prostacyclin. They play important physiological roles in the regulation of many processes e.g. vasodilation/vasoconstriction in the cardiovascular system. With respect to the cardiovascular system, thromboxane, a potent vasoconstrictor produced by platelets, is offset by prostacyclin, a potent vasodilator produced in the endothelium.

Nitric oxide (NO?) produced in blood vessels by the NO? synthases is another critical mediator of both physiologic and pathophysiologic processes in the regulation of vascular tone and inflammation. Atherosclerotic lesions contain increased levels of inducible COX (COX-2) and NO synthase (iNOS). Furthermore, recent developments show that both enzymes are bound, and thus, the fate of prostaglandin synthesis is linked to NO? and its higher oxides (NOx) derived from iNOS.

Given the complexity of NOx chemistry, ensuing studies on the effects of NOx on COX function have been controversial with reports of activation as well as inhibition. For example, peroxynitrite (ONOO-) activates COX and initiates cell-signaling events that lead to arachidonic acid release. ONOO- also nitrates a residue that is essential to COX catalysis (Tyrosine 385), leading to COX deactivation.

The principal studies in our laboratory are aimed at defining mechanisms by which NO? and prostaglandin synthetic pathways interact to alter prostaglandin biosynthesis as well as the impact of these mediators on atherosclerosis and thrombosis. There are opportunities in the laboratory to: 1) elucidate the mechanisms by which NOx species modulate prostaglandin production via post-translational modification of essential synthases in the arachidonic acid cascade and 2) define conditions that lead to COX regulation by iNOS during the development of atherosclerosis.