Our laboratory has discovered a cell-surface protein on cholesterol-loaded macrophages and smooth muscle cells (foam cells) that can mediate the specific binding, internalization, and degradation of lipoprotein(a)[Lp(a)] & apoprotein(a) [apo(a)]. Given the important role of foam cells in atherogenesis, the association of apo(a) & Lp(a) with atherosclerotic disease, and the co-localization of apo(a) with foam cells in lesions, we propose that this receptor influences the atherogenic potential of Lp(a) &apo(a) in the arterial wall. In preparation for exploring the role of this foam cell receptor, we have undertaken the cloning of the receptor and have mapped the region of apo(a) that binds to the receptor. In 1 of this proposal, we will complete the cloning of the receptor and use receptor probes to demonstrate its presence in atherosclerotic lesions. We have isolated clones of CHO cells that have defective Lp(a)/apo(a) receptor function by a combination of retroviral promoter-trap insertion mutagenesis and FACS sorting. Identification of the proviral integration sites in these clones will directly lead to the identification of the receptor genes and possibly other genes necessary for receptor function.
In aim 2, we will test the role of apo(a) & Lp(a) uptake by the foam cell receptors in atherogenesis by creating apo(a) & Lp(a) transgenic mice that: (i) express a mutant apo(a) that is defective in receptor binding but still retains the site that mediates the previously described atherogenic properties of apo(a); or (ii) express a truncated apo(a) that is a potent receptor ligand without with atherogenic site. Using a variety of atherosclerosis assays, these mice will be compared with non-transgenic mice and wild-type apo(a) & Lp(a) mice for the extent and properties of their lesions. The results of these experiments will be interpreted in the context of two opposing hypotheses: (1) uptake of apo(a)/Lp(a) in the arterial wall; or (2) uptake of apo(a)/Lp(a) by foam cells leads to a atherogenic responses in these cells. The studies in this proposal will lead to the molecular identification of a novel cholesterol-induced receptor on foam cells and should provide important insight into the role of foam cell-apo(a)/Lp(a) interactions in atherogenesis.
| Devlin, Cecilia M; Lee, Sung-Joon; Kuriakose, George et al. (2005) An apolipoprotein(a) peptide delays chylomicron remnant clearance and increases plasma remnant lipoproteins and atherosclerosis in vivo. Arterioscler Thromb Vasc Biol 25:1704-10 |
