Abstract
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. This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.
Highlights
This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, delaying plaque progression
Despite the long-standing notion that atherosclerosis is solely a cholesterol storage disease, recent clinical and experimental findings support a contemporaneous critical role for inflammation in atherosclerosis,[2] a hypothesis further strengthened by the outcome of the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study), which showed a reduction in adverse cardiovascular events in patients treated with an antibody against IL-1B.3
Atherosclerotic plaque formation and progression occur over many decades and involve monocyte/macrophage accumulation within the arterial wall, macrophage foam cell formation, consequent necrotic/lipid core establishment, and expansion, alongside vascular remodeling and extracellular
Summary
The data that support the findings of this study are available from the corresponding author upon reasonable request. Coronary artery segments were collected from cadaveric heart donors from the Bristol Valve Bank and incorporated into the Bristol Coronary Artery Biobank under National Research Ethics Service approval (08/H0107/48). The patients with histologically defined stable and unstable plaques (n=14/group) were of average age 56±2 and 59±2 years, respectively, and a 9/5 male–to-female ratio, as described previously.[23] Coronary artery plaques were histologically classified as stable or unstable through evaluation of intraplaque cellular content, lipid/ necrotic core size, and collagen amount, as shown to be effective delineators in human coronary plaque phenotyping[4,24] and as described previously.[23,25] Serial paraffin sections were immunolabeled with a CD (cluster of differentiation)-68 antibody to detect macrophages or αSMactin (alpha-smooth muscle actin) to distinguish vascular smooth muscle cells (VSMCs), alongside a galectin-3 antibody and the cells quantified.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
