Low density lipoprotein receptor-related protein mediates apolipoprotein E inhibition of smooth muscle cell migration.

Debi K Swertfeger,David Y Hui,Guojun Bu

doi:10.1074/jbc.m109124200

Abstract

This research was undertaken to identify the cell surface receptor responsible for mediating apolipoprotein E (apoE) inhibition of platelet-derived growth factor (PDGF)-directed smooth muscle cell migration. Initial studies revealed the expression of the low density lipoprotein receptor (LDLR), the LDL receptor-related protein (LRP), the very low density lipoprotein receptor (VLDL), and apoE receptor-2 in mouse aortic smooth muscle cells. Smooth muscle cells isolated from LDLR-null, VLDL-null, and apoE receptor-2-null mice were responsive to apoE inhibition of PDGF-directed smooth muscle cell migration, suggesting that these receptors were not involved. An antisense RNA expression knockdown strategy, utilizing morpholino antisense RNA against LRP, was used to reduce LRP expression in smooth muscle cells to assess the role of this receptor in apoE inhibition of cell migration. Results showed that apoE was unable to inhibit PDGF-directed migration of LRP-deficient smooth muscle cells. The role of LRP in mediating apoE inhibition of PDGF-directed smooth muscle cell migration was confirmed by experiments showing that antibodies against LRP effectively suppressed apoE inhibition of PDGF-directed smooth muscle cell migration. Taken together, these results document that apoE binding to LRP is required for its inhibition of PDGF-directed smooth muscle cell migration.

Highlights

The importance of apolipoprotein E1 in vascular protection has been recognized for a number of years [1, 2]
The results showed that whereas smooth muscle cells lacking the LDL receptors were less efficient in migration toward platelet-derived growth factor (PDGF) compared with cells containing the LDL receptor, apolipoprotein E (apoE) effectively inhibited PDGF-directed migration of smooth muscle cells obtained from both LDLRϩ/ϩ and LDLRϪ/Ϫ mice (Fig. 2)
Results of the current study documented that apoE inhibition of PDGF-directed smooth muscle cell migration is mediated via its binding to LDL receptor-related protein (LRP)

Summary

Introduction

The importance of apolipoprotein E (apoE) in vascular protection has been recognized for a number of years [1, 2]. Aside from its well documented function in mediating lipoprotein clearance by the liver [3], recent evidence suggests that apoE has direct cell regulatory functions in manners that are protective against vascular disease [4, 5] These include the modulation of inflammatory response by suppressing lymphocyte activation [6, 7], inhibiting agonist-induced platelet aggre-. ApoE stimulation of neurite outgrowth is independent of the LDL receptor and is mediated by apoE interaction with LRP [13, 25] Both immunosuppression and stimulation of neurite outgrowth by apoE are unrelated to its cholesterol-transporting properties because minimally lipidated or delipidated apoE are active in regulating these lymphocyte and neuronal cell functions [6, 22, 26]. We showed that apoE inhibits growth factor-induced smooth muscle cell

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Results

Conclusion