Cyclooxygenase (Cox) catalyzes the biologic oxidation of arachidonic acid into pro-inflammatory and angiogenic prostaglandins (PG). Enhanced PG synthesis is associated with inflammatory conditions', and inhibitors of the Cox enzyme are potent anti-inflammatory agents. Whereas PGE2 and PGE1 are inducers of angiogenesis in vivo, molecular mechanisms involved in PG-induced angiogenesis are not known. It is generally accepted that enhanced angiogenesis is a hallmark of many chronic inflammatory diseases and is necessary for the exponential phase of disease progression. Because PGs act transiently, the levels and activities of PG synthetic enzymes, particularly Cox, determine the bioactivity of PGs within tissues. Recent studies have shown that the Cox-1 and -2 genes are differentially expressed and regulated by angiogenic growth factors, cytokines and anti-inflammatory steroids. Furthermore, the regulation and expression of the Cox-2 gene suggests that it is important for pro- inflammatory and angiogenic events. This proposal is based on the premise that exaggerated and dysregulated expression of the Cox-2 gene within the inflammatory tissues is an important event that determines the evolution of the inflammatory disease phenotype, including angiogenesis. Molecular mechanisms involved in the expression of Cox genes at the level of transcription, post-transcriptional regulation, translational and post-translational regulation will be characterized in detail. In addition, the effects of Cox-2 overexpression on the angiogenic characteristics of endothelial cells in vitro and growth properties of fibroblasts will be assessed. The effects of exogenously applied and endogenously synthesized PGs on angiogenic gene expression in endothelial cells will also be assessed. Furthermore, the in vivo correlates of our in vitro findings will be studied in detail in the animal models of rheumatoid arthritis. These in vivo studies will focus on patterns of expression of Cox-1 and -2 gene products with respect to tissue locale, time and cell-specificity during the development of the inflammatory angiogenic disease. These studies are expected to further our understanding of the pathobiology of angiogenic chronic inflammatory diseases, processes that are fundamental to many human diseases.
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