Defensins are small cationic peptides secreted by activated human neutrophils that have been implicated in host defense against microorganisms. This application focuses on the potential role of human leukocyte defensins in the pathogenesis of atherosclerosis and thrombosis including their potential to promote the accumulation of Lp(a) in blood vessels, to stimulate smooth muscle cell proliferation and to inhibit plasminogen activation.
In Specific Aim 1 the mechanism by which defensin promotes the binding of Lp(a) to vascular cells and cell matrices in vitro will be examined. Two mechanisms by which defensin and defensin/Lp(a) complexes alter the in vitro behavior of vascular cells will be explored. 1.) Defensin and defensin/Lp(a) inhibit cellular fibrinolysis and attenuate plasmin and TFGb-mediated regulation of smooth muscle cell proliferation and 2.) Defensin retards the dissociation of Lp(a) from cell matrices and inhibits its internalization and degradation by vascular cells.
In Specific Aim 2, the role of defensin in vivo will be considered. First, the source of defensin synthesis in atherosclerotic human vessels will be examined. Second, the clearance, localization and turn-over of defensin and defensin/Lp(a) will be examined in normal mice. Third, the localization and turn-over of Lp(a) and effect of cholesterol feeding will be examined in a transgenic mouse that expresses human leukocyte defensin. Fourth, the effect of defensin and defensin/Lp(a) on the resolution of micropulmonary emboli will be measured. Finally, the interaction between endogenous defensin and endogenous Lp(a) will be examined in a novel transgenic mouse than overexpresses both human defensin and human Lp(a).