Abstract 12382: Galectin-3 Binding Protein Inhibits Macrophage Foam Cell Formation and Protects From Atherosclerosis
Rationale: Galectin-3 binding protein (Gal-3BP) is a secreted protein that modulates inflammation in vivo. In screening experiments we found Gal-3BP message overexpressed during macrophage foam cell formation, which is a crucial step during atherogenesis. Furthermore, Gal-3BP protein expression was found in many plaque macrophages from coronary artery disease patients.
Objective: We therefore hypothesized that Gal-3BP may affect atherogenesis through effects on macrophage foam cell formation.
Methods and Results: In vitro, recombinant Gal-3BP inhibited acLDL- and oxLDL-induced human macrophage foam cell formation in a time- and dose-dependent manner through downregulation of the scavenger receptors CD36 and SR-A. This effect was mediated by upregulation of the nuclear receptor NUR77. Conversely, macrophages from Nr4a1-/- mice lacking NUR77 showed increased oxLDL uptake. In vivo, recombinant murine Gal-3BP prevented monocyte recruitment as well as foam cell formation in a thioglycollate/acLDL/oxLDL-induced peritonitis model. Conversely, Lgals3bp-/- mice lacking Gal-3BP displayed significantly increased monocyte recruitment, foam cell formation and oxLDL uptake within the aortic wall. To test whether Gal-3BP promotes or reduces atherosclerosis, we crossed Lgals3bp-/- mice into the Apoe-/- background. At five weeks of western diet, we observed a 2.5-fold increase in aortic root lesion size and aortic macrophage content in Lgals3bp-/- Apoe-/- mice (n=4-6), suggesting that Gal-3BP may be atheroprotective.
Conclusions: We demonstrate that Gal-3BP inhibits macrophage foam cell formation through NUR77-dependent downregulation of the scavenger receptors CD36 and SR-A in vitro and in vivo. Furthermore, genetic deletion of the Lgals3bp gene coding for Gal-3BP lead to reduced atherosclerotic lesion formation. This identifies Gal-3BP as a novel constitutive endogenous modulator of macrophage foam cell formation suggesting novel therapeutic approaches in cardiovascular disease.
- © 2011 by American Heart Association, Inc.