Expression of LR11, a Mosaic LDL Receptor Family Member, Is Markedly Increased in Atherosclerotic Lesions

Abstract

Abstract —Receptors belonging to the LDL receptor (LDLR) family are thought to play key roles in lipoprotein metabolism in a variety of tissues, including the arterial wall. Here, we report that the expression of a 250-kDa mosaic LDLR family member, which we called LR11 for the presence of 11 ligand-binding repeats, is markedly induced during the process of atherogenesis in 2 animal models. Analysis by reverse transcription–polymerase chain reaction and RNase protection assays revealed that LR11 transcript levels rise in rabbit aortas displaying atheromatous lesions after the rabbits have been fed a high-cholesterol diet. Immunohistochemistry demonstrated that the highest induction of LR11 occurs in intimal smooth muscle cells (SMCs), followed by medial SMCs close to the intimal border of the atheromatous lesions. Experimental intimal hyperplasia by endothelial denudation showed that LR11 mRNA levels were also increased in the arteries after balloon injury, with the transcripts localized primarily in the hyperplastic intimal layer. In agreement with the correlation of LR11 induction during increased cell proliferation, cultured SMCs showed an increase in LR11 expression in the proliferative phase. Furthermore, Northern and Western blot analyses showed that medium conditioned by the monocyte-macrophage cell line THP-1 enhanced LR11 expression in cultured SMCs. These findings suggest that upregulation of LR11 might be contributing to the pathological roles of intimal and medial SMCs during arteriosclerotic lesion development and provide the first insight into the as yet unknown functional significance of this intriguing LDLR family member.