Research Overview
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. COX enzymes (also known as prostaglandin H2 synthase) initiate prostaglandin biosynthesis from the substrate arachidonic acid. Prostaglandins play important physiological roles in the regulation of many processes in major organ systems e.g. vasodilation/vasoconstriction in the cardiovascular system and salt and water excretion in the renal system. With respect to the cardiovascular system, thromboxane, a potent vasoconstrictor produced by platelets, is counterbalanced by prostacyclin, a potent vasodilator produced by the endothelium. Nitric oxide (NO) produced in arterial tissue by endothelial NO synthase or in smooth muscle cells by inducible NO synthase has similar biological properties to prostacyclin. In fact, prostaglandin and NO synthetic pathways converge to regulate the balance of prostaglandin production essential to cardiovascular function. Current studies are aimed at defining the mechanisms by which NO and its higher oxides (NOx) modify COX enzymes and regulate prostaglandin biosynthesis important to vascular reactivity. Given the diversity of NOx compounds and their chemistries, NOx post-translational modifications of COX enzymes are also diverse, and can have opposing effects on COX catalysis. Nitration, the covalent addition of NO2 to an aromatic carbon, is one modification that is associated with loss of enzymatic function and was demonstrated to occur in COX-1 from human atherosclerotic lesions. Recently, we described conditions that lead to differential nitration of purified COX-1 by the NOx species ONOO-. In particular, we showed that nitration of a residue that is essential to COX catalysis (Tyrosine 385), occurs by a heme-driven mechanism leading to COX deactivation. Ongoing studies are aimed at 1) elucidating mechanisms of COX post-translational modifications that occur in-vivo and under atherosclerotic conditions; 2) defining conditions in which the COX enzymes fail to produce biological response modifiers that are important to vascular reactivity.
