Monocytes have been shown to adhere to endothelium over lesions and lesion-prone areas, and migrate into the intima where subsequent activation and transformation to foam cell macrophages occur. The factors that induce monocytes to adhere to endothelium and migrate into the intima have not been identified. The objective of this study is to define the role of the monocyte/macrophage in atherogenesis by modifying monocyte/macrophage function and relating the altered function to foam cell lesion development in hypercholesterolemic rabbit. Preliminary studies have shown that specific thromboxane A2 (TXA2) inhibition in monocytes caused an increased synthesis of prostaglandin E2 (PGE2) which has been shown to modulate monocyte function. Furthermore, treatment of hypercholesterolemic rabbits with a TXA2 inhibitor significantly suppressed foam cell lesion development in a pilot study.
The aims of the study in this application are to identify the specific changes in arachidonic acid metabolism in the cells that are directly involved in early lesion development: monocytes, foam cell macrophages, endothelial and smooth muscle cells, and monocytes adherent to endothelium. These changes will be related to modulation of monocyte function, monocyte adherence to lesion-prone areas in vivo, and foam cell lesion development in hypercholesterolemic rabbits. The results from this study will help define the mechanism of early lesion development and will provide evidence as to whether monocyte infiltration in the intima is an important protective lipid-clearing mechanism, or possibly a pathologic one due to a focal accumulation of macrophages which are capable of further progressing lesion development.
