INJURY-COUPLED INDUCTION OF ENDOTHELIAL ENOS AND COX-2 GENES - A PARADIGM FOR THROMBORESISTANT GENE-THERAPY

Nitric oxide (NO) and prostacyclin (PGI(2) are potent molecules produc ed by endothelial cells that act synergistically to maintain normal va scular functions. Recent studies indicate that key enzymes that cataly ze the synthesis of these two molecules are induced by chemical and ph ysical factors. Because NO and PGI(2) and their synthetic enzymes have short half-lives, transcriptional induction by injurious agents, such as lysophosphatidylcholine (lysoPC), represents an important defense mechanism. LysoPC is capable of inducing constitutive endothelial NO s ynthase (eNOS) and cyclooxygenase-2 (COX-2), an immediate early gene, with distinct kinetics and possibly distinct transcriptional mechanism s. The importance of injury-coupled eNOS and COX overexpression in vas oprotection is supported by powerful effects of virus-mediated transfe r of COX and eNOS genes on defense against thrombosis and intimal hype rplasia in angioplasty-injured carotid arteries in animal models.