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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:831.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Accelerated Lipid-Induced Atherogenesis in Galectin-3-Deficient Mice

Role of Lipoxidation via Receptor-Mediated Mechanisms

Carla Iacobini; Stefano Menini; Carlo Ricci; Angela Scipioni; Viola Sansoni; Samantha Cordone; Maurizio Taurino; Matteo Serino; Giuseppe Marano; Massimo Federici; Flavia Pricci; Giuseppe Pugliese

From the Department of Clinical Sciences (C.I., S.M., C.R., A.S., V.S., S.C., G.P.), "La Sapienza" University; Unit of Vascular Surgery (M.T.), Sant’Andrea Hospital; Laboratory of Molecular Medicine (M.S., M.F.), Department of Internal Medicine, "Tor Vergata" University; and Departments of Drug Research and Evaluation (G.M.) and Cell Biology and Neurosciences (F.P.), National Institute of Health of Italy, Rome, Italy.

Correspondence to Giuseppe Pugliese, MD, PhD, Department of Clinical Sciences, Viale del Policlinico, 155-00161 Rome, Italy. E-mail giuseppe.pugliese{at}uniroma1.it

Objective— Modified lipoproteins, particularly oxidized LDLs, are believed to evoke an inflammatory response which participates in all stages of atherosclerosis. Disposal of these particles is mediated through receptors which may trigger proinflammatory signaling pathways leading to vascular injury. This study was aimed at assessing the role in atherogenesis of one of these receptors, galectin-3.

Methods and Results— Galectin-3-deficient and wild-type mice were fed an atherogenic diet or standard chow for 8 months. Lesion area and length were higher in galectin-3-deficient versus wild-type mice. At the level of the aortic sinus, wild-type animals showed only fatty streaks, whereas galectin-3-deficient mice developed complex lesions, associated with extensive inflammatory changes. This was indicated by the presence of T lymphocytes with activated Th1-phenotype and by more marked monocyte-macrophage infiltration, inflammatory mediator expression, vascular cell apoptosis, and proinflammatory transcription factor activation. Increased accumulation of oxidixed LDLs and lipoxidation products and upregulation of other receptors for these compounds, including the proinflammatory RAGE, were detected in galectin-3-deficient versus wild-type mice.

Conclusions— These data suggest a unique protective role for galectin-3 in the uptake and effective removal of modified lipoproteins, with concurrent downregulation of proinflammatory pathways responsible for atherosclerosis initiation and progression.

To assess the role of galectin-3 as a receptor for modified lipoproteins, mice lacking galectin-3 were fed an atherogenic diet. These animals showed accelerated atherosclerosis, with increased extent and particularly complexity of lesions and a distinct inflammatory phenotype, thus suggesting a protective scavenging and antiinflammatory role for galectin-3 in atherogenesis.

Key Words: atherosclerosis • inflammation • advanced lipoxidation end products • galectin-3 • RAGE