Published online before print March 1, 2007, doi: 10.1161/ATVBAHA.106.137091
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 American Heart Association, Inc.
Vascular Biology |
A Secreted Soluble Form of LR11, Specifically Expressed in Intimal Smooth Muscle Cells, Accelerates Formation of Lipid-Laden Macrophages
From the Departments of Clinical Cell Biology (K.O., Y.S.) and Genome Research and Clinical Application (H.B., M.J.), Chiba University Graduate School of Medicine, Chiba, Japan; Kowa Research Institute (H.Y.), Kowa Co Ltd, Higashimurayama, Japan; Department of Medical Biochemistry (W.J.S.), Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
Correspondence to Hideaki Bujo, Departments of Genome Research and Clinical Application Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail hbujo{at}faculty.chiba-u.jp
Objective— Macrophages play a key role in lipid-rich unstable plaque formation and interact with intimal smooth muscle cells (SMCs) in early and progressive stages of atherosclerosis. LR11 (also called sorLA), a member of low-density lipoprotein receptor family, is highly and specifically expressed in intimal SMCs, and causes urokinase-type plasminogen activator receptor-mediated degradation of extracellular matrices. Here we investigated whether the secreted soluble form of LR11 (solLR11) enhances adhesion, migration, and lipid accumulation in macrophages using animal models and cultured systems.
Methods and Results— Immunohistochemistry showed solLR11 expression in thickened intima of balloon-denuded rat artery. Macrophage infiltration into the cuff-injured artery was markedly reduced in LR11-deficient mice. In vitro functional assays using THP-1-derived macrophages showed that solLR11 (1 µg/mL) significantly increased acetylated low-density lipoprotein uptake by THP-1 cells and cell surface levels of scavenger receptor SR-A 1.7- and 2.8-fold, respectively. SolLR11 dose-dependently increased the migration activity of THP-1 macrophages and adhesion to extracellular matrices 2.0- and 2.1-fold, respectively, at 1 µg/mL. These effects of solLR11 were almost completely inhibited by a neutralizing anti-urokinase-type plasminogen activator receptor antibody.
Conclusion— SolLR11, secreted from intimal SMCs, regulates adhesion, migration, and lipid accumulation in macrophages through activation of urokinase-type plasminogen activator receptor. The formation of lipid-laden macrophages in atherosclerotic plaques possibly is regulated by SolLR11 of intimal SMCs.
LR11 is secreted from intimal SMCs in a soluble form. Here we report that solLR11 modulates multiple functions of macrophages toward increased adhesion, migration, scavenger receptor expression, and uptake of modified lipid. This functional characterization of solLR11 provides novel insights into the pathophysiological significance of intimal SMCs in the regulation of macrophage function.
Key Words: atherosclerosis • foam cells • macrophages • scavenger receptors • smooth muscle cells
This article has been cited by other articles:
 |
|
 |
|
  S. K. Nilsson, S. Christensen, M. K. Raarup, R. O. Ryan, M. S. Nielsen, and G. Olivecrona Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families J. Biol. Chem., September 19, 2008; 283(38): 25920 - 25927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q.-L. Ma, B. Teter, O. J. Ubeda, T. Morihara, D. Dhoot, M. D. Nyby, M. L. Tuck, S. A. Frautschy, and G. M. Cole Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer's Disease (AD): Relevance to AD Prevention J. Neurosci., December 26, 2007; 27(52): 14299 - 14307. [Abstract] [Full Text] [PDF]
|
|