Research Overview
Research is focused on understanding how the function of the enzyme cyclooxygenase (COX) is altered during atherosclerosis (a disease that causes thickening of the arterial wall and is responsible for more deaths in the U.S. than any other condition). COX enzymes (which are inhibited by aspirin) are responsible for producing prostaglandins that have opposing effects in the blood vessel wall, e.g. vasodilatation versus constriction. Our hypothesis is that during atherosclerosis, the delicate balance of prostaglandins is disturbed by mechanisms not yet understood. We propose that nitric oxide (NO; also an important vasodilatator in the blood vessel wall) and other NO-related species modulate COX activity. In this regard, our studies have explored the mechanisms of interaction between the NO and COX metabolic pathways at the purified enzyme level, in cellular systems, and in murine and human atherosclerotic tissue. Studies to date have demonstrated that peroxynitrite, which is formed under disease conditions by the reaction of NO and superoxide anion, has opposing effects on COX activity: (i) peroxynitrite activates COX metabolism of arachidonic acid to prostaglandins by oxidizing the heme and thereby initiating catalysis, (ii) peroxynitrite also acts on signaling pathways that lead to arachidonic acid release in vascular cells, and (iii) in the absence of arachidonic acid, peroxynitrite nitrates tyrosine (Tyr) residues in COX with the result that enzyme activity is diminished. Using purified enzyme, the site of peroxynitrite nitration has been demonstrated to be tyrosine 385. Importantly, we have discovered that COX enzyme in human and murine atherosclerotic tissue is nitrated, and that COX nitration in a murine model of atherosclerosis is dependent on nitric oxide released from the inducible form of nitric oxide synthase (iNOS). Thus, our findings indicate that NO-related species mediate the function of COX enzymes such that the prostaglandin profile in the blood vessel wall may become disturbed during atherosclerosis.
