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

Abstract Nitric oxide (NO) and prostacyclin (PGI2) are potent molecules produced by endothelial cells that act synergistically to maintain normal vascular functions. Recent studies indicate that key enzymes that catalyze the synthesis of these two molecules are induced by chemical and physical factors. Because NO and PGI2 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 synthase (eNOS) and cyclooxygenase-2 (COX-2), an immediate early gene, with distinct kinetics and possibly distinct transcriptional mechanisms. The importance of injury-coupled eNOS and COX overexpression in vasoprotection is supported by powerful effects of virus-mediated transfer of COX and eNOS genes on defense against thrombosis and intimal hyperplasia in angioplasty-injured carotid arteries in animal models.