LDL Receptor–Related Protein and the Vascular Wall

Abstract

Abstract-LDL receptor-related protein 1 (LRP1) is highly expressed in the vascular wall and is mainly associated with macrophages and vascular smooth muscle cells (VSMCs). Overexpression of LRP1 in atherosclerotic lesions has been demonstrated in several animal models and human lesions. Clinical studies have suggested a relation between alterations in LRP1 expression and coronary heart disease. Indeed, it has been demonstrated that LRP1 gene expression is increased in blood mononuclear cells from patients with coronary obstruction and that the LRP1 mRNA-protein expression ratio is altered in coronary patients. Taken together, these results seem to suggest that LRP1 may be a pivotal receptor in the etiology of atherosclerosis. Our group has contributed to the elucidation of the physiopathologic role of LRP1 in the vascular wall by demonstrating that LRP1-mediated, matrix-retained LDL internalization could be crucial for VSMC-foam cell formation, that LRP1 is upregulated by lipid during human atherosclerotic lesion progression, and that LRP1-mediated aggregated LDL uptake causes the prothrombotic transformation of the vascular wall. Therefore, LRP1 seems to play a pathologic function during atherosclerotic lesion progression; however, LRP1 also seems to be essential for embryonic development and for the maintenance of vascular integrity. The protective effect of LRP1 in the vessel wall seems to be mainly due to its role in controlling certain signaling pathways. In this review, we will focus on the description of the main physiopathologic functions of LRP1 in the vascular wall. . Although macrophage-foam cell formation has been extensively studied, little is known about how VSMCs become foam cells. Macrophages become foam cells through the uptake of diversely modified LDLs, whereas the mechanism of lipid accumulation in the intima and its uptake by VSMCs was not fully elucidated until recently. In VSMCs, the LDL receptor is downregulated by excess LDL and the scavenger receptors are barely expressed, whereas LDL receptor-related protein 1 (LRP1) is highly expressed. Aggregates of LDL (agLDL) generated in vitro by vortexing have similar physicochemical characteristics to those found in the vessel wall retained by extracellular matrix proteoglycans. 1,2 Our results clearly showed that these agLDLs induced cholesterol accumulation in human coronary VSMCs up to the level considered the hallmark of foam cell formation. Fluorescence microscopy experiments revealed that agLDLs were internalized in diffuse and large vesicles, which were clearly different from the smaller, well-defined vesicles involved in normal LDL uptake. 3,4 This result suggested a different pathway for the internalization of agLDLs. We hypothesized that the particular structure of the LRP1, composed of multiple copies of 3 of the 4 structural motifs found in the extracellular binding domain of the LDL receptor, would facilitate the interaction with agLDL, composed of hundreds of LDL particles. Indeed, immunocytochemistry and fluorescence microscopy an...

Localization of multiple pleiotropic genes for lipoprotein metabolism in baboons

“…LRP1 is ubiquitously expressed and functions in endocytosis and signal transduction (35,45). In binding and internalizing a number of lipoprotein ligands, LRP1 plays a key role in atherosclerosis (46). ApoF is a lipoprotein constituent that is an inhibitor of cholesteryl ester transfer protein; its presence on lipoproteins modulates cholesteryl ester transfer protein-mediated remodeling between VLDL and both LDL and HDL particles (47,48).…”

Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

“…Overexpression of LRP5 is found in infiltrated macrophages of human advanced coronary atherosclerotic plaques 22, and LRP1 ‐overexpression has been reported in atherosclerotic lesions both in animal models and human lesions 63, 64, 65, 66. Interestingly, in PBL of FH patients with atherosclerotic lesions (FH‐AT), the expression level of transcripts for LRP1 , LRP5 and LRP6 was similar in patients with atherosclerotic burden in one or more arterial beds (Fig.…”

Identification of candidate genes encoding an LDL-C QTL in baboons

“…Further, we validated expression of candidate proteins using Western discordant between low and high LDL-C responders and therefore were candidates encoding the LDL-C concentration QTL. Notably, Sp1 transcription factor ( SP1 ), apolipoprotein F ( APOF ), sterol O -acyltransferase 2 ( SOAT2 ), and LDL receptor-related protein 1 ( LRP1 ), implicated in lipoprotein metabolism (20)(21)(22)(23)(24), were not differentially expressed in response to the HCHF diet challenge in our study. Our fi ndings suggest we have identifi ed novel candidate genes involved in lipid metabolism-related pathways.…”