Published online before print November 1, 2004, doi: 10.1161/01.CIR.0000147181.65298.4D
(Circulation. 2004;110:3121-3128.)
© 2004 American Heart Association, Inc.
Molecular Cardiology |
Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction
From the Experimental and Molecular Cardiology Laboratory, Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM) (U.C.S., S.P., J.H.v.B., B.S., H.J.G.M.C., Y.M.P.), the Department of Cardiothoracic Surgery, University Hospital Maastricht (U.C.S., T.J.v.B., J.M.), and the Department of Pathology, CARIM, University of Maastricht (J.P.M.C.), Maastricht, the Netherlands; and the Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians University, Munich, Germany (S.A., H.-J.G.).
Correspondence to Yigal M. Pinto, MD, PhD, Experimental and Molecular Cardiology, Department of Cardiology, 6202 AZ Maastricht, The Netherlands. E-mail y.pinto{at}carim.unimaas.nl
Received April 14, 2004; revision received August 18, 2004; accepted August 23, 2004.
Background— Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF.
Methods and Results— In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction.
Conclusions— This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.
Key Words: angiotensin • collagen • fibroblasts • heart failure
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