An excessive inflammatory reaction following injury to vessel wall is now believed to be the major factor in atherogenesis. Phospholipase A2s (PLA2s), a group of rate-limiting enzymes for production of arachidonic acid, play an important role in inflammation. Among the many types of PLA2s identified to date, evidence indicates for an involvement of both cytosolic and secretary type PLA2s (cPLA2 and sPLA2s) in inflammation. Activation of these PLA2s in dysfunctional endothelial cells, via production of arachidonic acid, the precursor for eicosanoids, can trigger a cascade of events, including induction of expression of cell adhesion molecules, that, in turn, may result in recruitment of immune cells (leukocytes and monocytes) to the site of vascular injury/infection as well as migration of vascular smooth muscle cells (VSMC) from media to intima. Transmigration of immune cells into sub-endothelial space and their activation also results in the production of a variety of molecules, including cytokines, eicosanoids, peptide growth factors and reactive oxygen species. Many of these molecules are both chemotactic and mitogenic to VSMC, and therefore, may provide a chain of cues for continued migration of these cells from media to intima and their multiplication in intima leading to neointima formation. In this aspect, our preliminary results, for the first time, reveal that Jak/STAT-dependent cPLA2 expression and arachidonic acid release are involved in VSMC migration induced by receptor tyrosine kinase (RTK) agonist, platelet-derived growth factor-BB (PDGF-BB). Based on this novel and exciting finding, we suspect an important role for cPLA2 in VSMC migration from media to intima in response to various bioactive molecules that are produced at the site vascular injury, and thereby, contribute to neointima formation. We will test this hypothesis by addressing the following three specific aims: 1. To study the role of cPLA2 in RTK and G protein-coupled receptor (GPCR) agonist-induced VSMC migration. 2. To study the role of the Jak-STAT pathway in RTK and GPCR agonist-induced cPLA2 expression, arachidonic acid release and VSMC migration. 3. To study the role of cPLA2 and the Jak/STAT pathway in VSMC migration, proliferation and neointima formation in models of rat and/or mouse vascular injury. The results of the above three specific aims will provide novel information in regard to the role of cPLA2 and Jak/STAT signaling in VSMC migration and neointima formation. Such knowledge will be useful in the development of potential therapeutics targeting inflammatory vascular diseases such as atherosclerosis and restenosis.
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