Lipoprotein(a) and Atherosclerosis

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DESCRIPTION (provided by applicant): Lp(a) is composed of apo(a) and LDL. The apo(a) and apoB-100 of the LDL are covalently linked. Plasma concentrations of Lp(a), in excess of 30 mg/dl, are atherogenic, whereas LDL is atherogenic only at much higher concentrations. Therefore, Lp(a) is more atherogenic than one would expect from its content of LDL. However, the mechanisms by which Lp(a) contributes to the development of atherosclerosis are poorly understood, in part because of the lack of murine models expressing high levels of Lp(a). We have recently overcome this obstacle by generating mice with high-level hepatic expression of apo(a) and crossing them with mice that express physiological levels of human apoB-100. The plasma of these mice contains Lp(a) and little if any nonassociated LDL. These mice will therefore provide an excellent model to dissect the mechanisms by which Lp(a) contributes to atherosclerosis. We will test the hypothesis that proteoglycan binding of Lp(a) mediated by apoB-100 and fibrin binding of Lp(a) mediated by the apo(a) component contribute to the atherogenicity of Lp(a). To test this hypothesis, we generated mice with high-level hepatic expression of either wild-type apo(a) or a mutant form of apo(a) that is lysine-binding-defective (LBD). In Specific Aim 1, we will breed these mice with mice expressing proteoglycan-binding-defective LDL. We will therefore have mice with wild-type Lp(a), proteoglycan-binding-defective Lp(a), LBD Lp(a), and proteoglycan-binding-defective/LBD Lp(a). In Specific Aim 2, we will characterize these forms of Lp(a), demonstrate their properties, and assess their effects on lipid and lipoprotein profiles. We will also follow up on our intriguing observation that Lp(a) contains high levels of oxidized phospholipid, whereas LDL expressed at the same level do not. In Specific Aim 3, we will evaluate the contribution of proteoglycan and fibrin binding by Lp(a) to the development of atherosclerosis in this mouse model. In addition, we will determine if the oxidized phospholipid in Lp(a) contributes to its atherogenicity. The proposed studies will increase our understanding of the mechanisms by which Lp(a) contributes to atherogenesis and may lead to more rational means of intervention.