Abstract
Cyclooxygenase (COX)-derived prostaglandins (PGs) and nitric oxide (NO) play physiological and pathological roles in many processes e.g. vasodilation/vasoconstriction. In fact, PG and NO synthetic pathways converge to regulate PG production essential to vascular function. Recently, we showed that differential nitration and aggregation of COX-1 by peroxynitrite (ONOO−) occurs. We found that nitration at tyrosine 385 (essential to catalysis) is heme-driven and leads to COX deactivation. The following study assesses ONOO−-modifications to COX-1 and its activity in physiological bicarbonate levels, in the presence and absence of heme, arachidonic acid, aspirin and the hydroperoxide scavenger glutathione peroxidase. When heme in COX-1 was substituted with CoIII-protoporphyrinIX, ONOO−-treatment caused minimal nitration and aggregation, confirming the role of the Fe center in deactivation processes. Physiological bicarbonate levels markedly increased nitration levels in apoCOX-1 and holoCOX-1 compared to other buffers, without altering apoCOX-1 function. This result supports specific and heme-decisive tyrosine nitration that leads to COX-1 inactivation. Results also indicate that while arachidonic acid protects against nitration by ONOO−, aggregation is driven by arachidonic acid-hydroperoxides suggesting that ONOO−-induced COX-1 modifications are regulated by arachidonic acid. Supported by the NIH (HL46403 and HL07423), Pfizer Inc., Philip Morris USA Inc. and Philip Morris International.
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