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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:433.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Galectin-3 Is an Amplifier of Inflammation in Atherosclerotic Plaque Progression Through Macrophage Activation And Monocyte Chemoattraction

Marianna Papaspyridonos; Eileen McNeill; Joe P. de Bono; Alberto Smith; Kevin G. Burnand; Keith M. Channon; David R. Greaves

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.

Correspondence to David R Greaves, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE. 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 of 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.

Galectin-3 was upregulated in advanced human and murine ApoE^–/– atherosclerotic plaques. Mediators released in response to Gal-3 treatment in macrophages increased monocyte chemotaxis, and microarray analysis confirmed the upregulation of several key chemoattractant molecules. Gal-3 is an amplifier of inflammation that could be used as a marker of atherosclerotic plaque progression or target for atherosclerosis.

Key Words: galectin-3 • chemokines • atherosclerosis • macrophages • inflammation

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