Atherosclerosis, chronic inflammatory process progressing from fatty lesions to fibrous and unstable plaques, is the major underlying factor in most cases of coronary heart disease. Clinical disease as a result of atherosclerotic disease remains as the leading determinant for the extensive mortality and morbidity. and exorbitant health care costs in our society. The """"""""LDL oxidation"""""""" hypothesis has gained general acceptance as a leading player in atherogenesis and it is recognized that oxidized LDL exhibits many pro-atherogenic properties. properties. The factors that initiate LDL, oxidating in vivo are poorly understood. However, circumstantial evidence has placed the 12/15-lipoxygenase in the context of atherosclerosis. Thus, in the first specific aim, the role of 12/15- lipoxygenase in mouse models of atherosclerosis (apoB editing catalytic polypeptide-1 (apobec-1)/LDL-receptor deficient and apoE deficient) will be assessed by quantitating lesion development throughout the aorta by the """"""""en face"""""""" method using appropriately crossbred 12/15-lipoxygenase deficient mice. The combined effects of the anti-oxidant vitamin E with 12/15-lipooxygenase deficiency will also be examined. Total cholesterol, triglycerides, lipoprotein profiles and oxidative stress markers known as isoprostanes will be measured and correlated with lesion development. If specific 12/15-lipoxygenase inhibitors are ultimately to be used in atherosclerotic disease management they will need to be effective in limiting, or causing regression of, pre-existing lesion. By using an inducible 12/15-lipoxygenase gene disruption strategy in mice with atherosclerosis at various stages this important matter will be addressed.
In specific aim 2, the subset of macrophages expressing 12/15- lipoxygenase will be characterized and purified. The effects of lipid loading and factors regulating 12/15-lipoxygenase gene expression will be determined.
In specific aim 3, the novel 12(R)-lipoxygenase will be characterized and its relevance to atherosclerosis and LDL oxidation discerned.
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