Atherosclerotic vascular disease is a leading cause of death in patients with Type 2 diabetes. A key event in vessel plaque formation is interaction between monocytes and endothelial cells. This project will greatly expand upon the exciting observation made in the previous funding period that high glucose (HG) and products of the 12- lipoxygenase (12-LO) pathway selectively increase monocyte adhesion to human aortic endothelial cells (HAEC). The overall hypothesis to be tested is that glucose and the diabetic state induces LO expression and activity in aortic endothelial cells and that arachidonic or linoleic acid- derived oxidative lipids activate key signal transduction pathways leading to the binding of monocytes to the endothelium. The project will utilize novel ribozymes and mouse models to mechanistically evaluate the role of 12-LO in this process.
Aim #1 will focus on the mechanisms by which HG increases LO products in HAEC.
Aim #2 will explore the signaling mechanisms for how HG and LO products act in HAEC to increase monocyte:endothelial interactions. The role of MAP kinase pathway, reactive oxygen species, and key transcription factors will be explored.
Aim #3 will evaluate whether HG and LO products act in HAEC to increase monocyte: endothelial interactions. The role of MAP kinase pathways, reactive oxygen species, and key transcription factors will be explored.
Aim #3 will evaluate whether HG and LO products induce inflammatory cytokines such as IL-8, chemotactic factors such as RANTES, or modify nitric oxide activity in HAEC.
Aim #4 will explore the mechanism and effects of a novel anti-inflammatory agent, lisofylline, on reducing HG and LO-mediated monocyte adhesion to HAEC. Finally, we will use transgenic and knockout models of 12-LO to evaluate the role of LO in mediating monocyte:endothelial interactions and atherogenesis in vivo. The project will also evaluate endothelial cells and monocytes from the unique porcine models available in the Swine Core. The project will closely interact with projects 1, 3, and 4. These studies will greatly advance our understanding of how diabetes can accelerate the early stage of atherosclerosis. The results should provide the rationale for new therapeutic advances in this area.
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