Abstract TMP112: F11 Receptor Antagonists As Therapeutic Agents For Atherosclerosis And Thrombosis
Rationale and Objective: The F11 Receptor (F11R; aka Junctional Adhesion Molecule-A, JAM-A) is a cell adhesion protein present on the surface of circulating platelets and within tight junctions of endothelial cells (EC). We reported evidence for the critical role of F11R in the adhesion of platelets to cytokine-inflamed endothelium. Because platelet adhesion to an inflamed endothelium is one of the early steps of plaque formation in non-denuded blood vessels, we concluded that exposure of de novo synthesized F11R molecules on the luminal surface of EC is a crucial step in early stages of atherogenesis, leading to atherosclerosis, heart attacks and strokes. Utilizing recombinant F11R protein and F11R peptides, we have demonstrated that the expression of F11R on the luminal surface of inflamed EC initiates platelet adhesion to the inflamed EC thru binding of F11R molecules and this binding is inhibited by F11R antagonists. The present report provides new in-vivo evidence for the critical role of F11R antagonists in the formation of atherosclerotic plaques in apoE-/- mice.
Methods and Results: The effect of F11R peptide on the formation of atherosclerotic plaques was determined in apoE -/- mice from 12 to 20 weeks of age. Fourteen apoE-/- mice were obtained from the Jackson Laboratory and fed a Western-type diet. Seven mice were injected with an F11R peptide (4.3 mg/100μl) every day for either a 3-, 4- or a 5- month period. Control animals were injected with diluent for the same period of time. The aortae and hearts were dissected and the aortic arch was photographed. An aortic lesion en face assay and morphometric lesion analysis was performed. Mice treated with the F11R peptide demonstrated healthy appearance with significantly decreased atherosclerotic lesion size as compared to unhealthy, control animals with large lesion sizes.
Conclusions: F11R peptide inhibits the development of plaque formation in Apo E-/- mice, an animal model of atherosclerosis. The results of combined in vitro and in vivo studies provide information that development of small peptide analogs or peptidiomimetics which antagonize the pathological activity of F11R can be used as therapeutic agents for the prevention of atherosclerosis and thrombosis leading to heart attacks and strokes.
- © 2012 by American Heart Association, Inc.