on December 20, 2007
Published online before print December 20, 2007, doi: 10.1161/ATVBAHA.107.159160
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Submitted on August 3, 2007
Accepted on December 3, 2007
Galectin-3 Is an Amplifier of Inflammation in Atherosclerotic Plaque Progression Through Macrophage Activation And Monocyte Chemoattraction
Marianna Papaspyridonos ;
From the Sir William Dunn School of Pathology (M.P., D.R.G.), University of Oxford; the Department of Cardiovascular Medicine (E.M., J.P.d.B., K.M.C.), University of Oxford; and the Academic Department of Surgery (A.S., K.G.B.), Cardiovascular Division, King’s College, London, UK.
* To whom correspondence should be addressed. E-mail: david.greaves{at}path.ox.ac.uk.
Objective—Galectin-3 (Gal-3) is a 26-kDa lectin known to regulate many aspects of inflammatory cell behavior. We assessed the hypothesis that increased levels of Gal-3 contribute to atherosclerotic plaque progression by enhancing monocyte chemoattraction through macrophage activation.
Methods and Results—Gal-3 was found to be upregulated in unstable plaque regions of carotid endarterectomy (CEA) specimens compared with stable regions from the same patient (3.2-fold, P<0.05) at the mRNA (n=12) and (2.3-fold, P<0.01) at the protein level (n=9). Analysis of aortic tissue from ApoE-/- mice on a high fat diet (n=14) and wild-type controls (n=9) showed that Gal-3 mRNA and protein levels are elevated by 16.3-fold (P<0.001) and 12.2-fold (P<0.01) and that Gal-3 staining colocalizes with macrophages. In vitro, conditioned media from Gal-3–treated human macrophages induced an up to 6-fold increase in human monocyte chemotaxis (P<0.01, ANOVA), an effect that was reduced by 66 and 60% by Pertussis Toxin (PTX) and the Vaccinia virus protein 35K, respectively. Microarray analysis human macrophages and subsequent qPCR validation confirmed the upregulation of CC chemokines in response to Gal-3 treatment.
Conclusions—Our data suggest that Gal-3 is both a marker of atherosclerotic plaque progression and a central contributor to the pathology by amplification of key proinflammatory molecules.
Key words: galectin-3 • chemokines • atherosclerosis • macrophages • inflammation
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