Affiliation:
1. From the Laboratory of Cardiovascular Pathology, Bristol Medical School, Faculty of Health Sciences, University of Bristol, England.
Abstract
Objective:
Galectin-3 (formerly known as Mac-2), encoded by the
LGALS3
gene, is proposed to regulate macrophage adhesion, chemotaxis, and apoptosis. We investigated the role of galectin-3 in determining the inflammatory profile of macrophages and composition of atherosclerotic plaques.
Approach and Results:
We observed increased accumulation of galectin-3–negative macrophages within advanced human, rabbit, and mouse plaques compared with early lesions. Interestingly, statin treatment reduced galectin-3–negative macrophage accrual in advanced plaques within hypercholesterolemic (apolipoprotein E deficient)
Apoe
−/−
mice. Accordingly, compared with
Lgals3
+/+
:
Apoe
−/−
mice,
Lgals3
−/−
:
Apoe
−/−
mice displayed altered plaque composition through increased macrophage:smooth muscle cell ratio, reduced collagen content, and increased necrotic core area, characteristics of advanced plaques in humans. Additionally, macrophages from
Lgals3
−/−
mice exhibited increased invasive capacity in vitro and in vivo. Furthermore, loss of galectin-3 in vitro and in vivo was associated with increased expression of proinflammatory genes including MMP (matrix metalloproteinase)-12, CCL2 (chemokine [C-C motif] ligand 2), PTGS2 (prostaglandin-endoperoxide synthase 2), and IL (interleukin)-6, alongside reduced TGF (transforming growth factor)-β1 expression and consequent SMAD signaling. Moreover, we found that MMP12 cleaves macrophage cell-surface galectin-3 resulting in the appearance of a 22-kDa fragment, whereas plasma levels of galectin-3 were reduced in
Mmp12
−/−
:
Apoe
−/−
mice, highlighting a novel mechanism where MMP12-dependent cleavage of galectin-3 promotes proinflammatory macrophage polarization. Moreover, galectin-3–positive macrophages were more abundant within plaques of
Mmp12
−/−
:
Apoe
−/−
mice compared with
Mmp12
+/+
:
Apoe
−/−
animals.
Conclusions:
This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
45 articles.
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