The lipoprotein Lp(a) is a large cholesterol-rich particle that has been identified as a major risk factor for atherosclerosis. While the physiological role of Lp(a) is not known, it has been speculated to deliver cholesterol to cells at wound sites, a function that may become pathological when plasma levels of Lp(a) are high. Lp(a) is distinguished from low density lipoprotein (LDL) by the presence of apolipoprotein (a), which is homologous to plasminogen. The mechanisms of Lp(a) atherogenicity have not been elucidated, but two different hypotheses have been proposed to account for the association of elevated Lp(a) with atherosclerosis. In the first case, several investigators have found that Lp(a) competes for plasminogen binding sites to cells, and have postulated that this property of Lp(a) contributes to the atherogenic process by reducing the extent of plasmin formation thereby reducing fibrinolysis. Reduced plasmin activity may also reduce the production of TGFbeta, a molecule that prevents smooth muscle cell migration. In support of this notion, mice expressing apo(a) appear to have reduced capacity to activate TGFbeta on the vessel wall. Alternatively, the second hypothesis focuses on the lipid-bound form of apo(a) in the Lp(a) particle, and suggests that the Lp(a) particle could contribute to cholesterol deposition and foam cell formation due to its avid binding to cellular receptors. To date the identity of the macrophage receptors that mediate the uptake of Lp(a) leading to cholesterol accumulation and degradation of the apolipoproteins remain unknown. Recent data suggests that this role may be filled by the VLDL receptor, an endocytic receptor that is a member of the LDL receptor superfamily, whose expression is up- regulated in lesion macrophages. The hypothesis of this application is that the VLDL receptor recognizes certain isoforms of Lp(a) and mediates their catabolism and that this process can lead to cellular accumulation of lipid within lesion macrophages. These hypotheses will be tested in the following specific aims: 1) Determine if the VLDL receptor selectively recognizes certain isoforms of Lp(a), and define the basis for the apparent selectivity. 2) Define the role of the VLDL receptor in the catabolism of Lp(a) in a mouse model. 3) Determine if the VLDL receptor contributes to the atherogenicity of Lp(a) in a mouse model. 4) Investigate mechanisms that regulate gene expression of the VLDL receptor in macrophages.
