Abstract 316: Deficiency in the Low-Density Lipoprotein Receptor-Related Protein 8 Alters Macrophage Function and Promotes Atherosclerotic Plaque Necrosis

Abstract

The low-density lipoprotein receptor-related protein 8 (Lrp8; apolipoprotein E receptor 2; ApoER2) is a member of the low-density lipoprotein receptor ( Ldlr ) gene family which is predominately expressed in the brain, but is also expressed in vascular cells and macrophages where its function is currently unknown. Genomewide linkage analysis has associated a single nucleotide polymorphism in the LRP8 gene with familial and premature coronary artery disease and myocardial infarction in humans, suggesting that Lrp8 may contribute to atherosclerosis. This study assessed the role of Lrp8 in macrophage function and atherosclerosis. Following 24 weeks on a high-fat, high-cholesterol Western-type diet, lesion sizes were similar between Lrp8 knockout mice on an Ldlr deficient background ( Lrp8 -/- Ldlr -/- ) and Ldlr single knockout ( Ldlr -/- ) mice, but more complex lesions with extensive necrosis were observed in the Lrp8 -/- Ldlr -/- mice. The differences in lesion composition were not due to differences in plasma cholesterol levels, but increased expression of the macrophage marker CD68 in the Lrp8 -/- Ldlr -/- lesions suggested that these differences were due to alterations in macrophage function. When compared to wild-type (WT) cells, mRNA levels of the nuclear receptor PPARγ and PPARγ-responsive genes such as Cd36, Abca1 , and Lrp1 were significantly increased in Lrp8 deficient macrophages. Additionally, the expression of inducible nitric oxide synthase (iNOS) and Ldlr were reduced in Lrp8 deficient macrophages compared to WT cells. Furthermore, following 24 hours in culture there was a reduced number of adherent macrophages found in the Lrp8 deficient population compared to the WT cells. Consistent with this, phosphorylation of Akt was reduced while phosphorylation of p53 was increased in Lrp8 deficient macrophages, suggesting that Lrp8 may affect macrophage viability and proliferation via modulation of cell signaling events. Taken together, these data suggest that Lrp8 plays a critical role in macrophage function via regulation of foam cell formation as well as cell proliferation and viability, with reduced expression of Lrp8 significantly contributing to the pathogenesis of atherosclerosis and lesion necrosis.