This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 110/19/3121    most recent 01.CIR.0000147181.65298.4Dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sharma, U. C. Articles by Pinto, Y. M. Search for Related Content PubMed PubMed Citation Articles by Sharma, U. C. Articles by Pinto, Y. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Cardiomyopathy Heart Failure Related Collections Cardio-renal physiology/pathophysiology Remodeling Animal models of human disease Hypertrophy Physiological and pathological control of gene expression

(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

Umesh C. Sharma, MB BS, MSc; Saraswati Pokharel, MB BS; Thomas J. van Brakel, MD; Jop H. van Berlo, MD; Jack P.M. Cleutjens, PhD; Blanche Schroen, MSc; Sabine André, PhD; Harry J.G.M. Crijns, MD, PhD; Hans -J. Gabius, PhD; Jos Maessen, MD, PhD; Yigal M. Pinto, MD, PhD

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

This article has been cited by other articles:

				U. Sharma, N.-E. Rhaleb, S. Pokharel, P. Harding, S. Rasoul, H. Peng, and O. A. Carretero Novel anti-inflammatory mechanisms of N-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1226 - H1232. [Abstract] [Full Text] [PDF]

				A. C. MacKinnon, S. L. Farnworth, P. S. Hodkinson, N. C. Henderson, K. M. Atkinson, H. Leffler, U. J. Nilsson, C. Haslett, S. J. Forbes, and T. Sethi Regulation of Alternative Macrophage Activation by Galectin-3 J. Immunol., February 15, 2008; 180(4): 2650 - 2658. [Abstract] [Full Text] [PDF]

				N. C. Henderson, A. C. Mackinnon, S. L. Farnworth, T. Kipari, C. Haslett, J. P. Iredale, F.-T. Liu, J. Hughes, and T. Sethi Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis Am. J. Pathol., February 1, 2008; 172(2): 288 - 298. [Abstract] [Full Text] [PDF]

				S. S. Palaniyandi, Y. Nagai, K. Watanabe, M. Ma, P. T. Veeraveedu, P. Prakash, F. A. Kamal, Y. Abe, K. Yamaguchi, H. Tachikawa, et al. Chymase Inhibition Reduces the Progression to Heart Failure After Autoimmune Myocarditis in Rats Experimental Biology and Medicine, October 1, 2007; 232(9): 1213 - 1221. [Abstract] [Full Text] [PDF]

				K. Reifenberg, H.-A. Lehr, M. Torzewski, G. Steige, E. Wiese, I. Kupper, C. Becker, S. Ott, P. Nusser, K.-I. Yamamura, et al. Interferon-{gamma} Induces Chronic Active Myocarditis and Cardiomyopathy in Transgenic Mice Am. J. Pathol., August 1, 2007; 171(2): 463 - 472. [Abstract] [Full Text] [PDF]

				W.H. Wilson Tang, G. S. Francis, D. A. Morrow, L. K. Newby, C. P. Cannon, R. L. Jesse, A. B. Storrow, R. H. Christenson, COMMITTEE MEMBERS, R. H. Christenson, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure Circulation, July 31, 2007; 116(5): e99 - e109. [Full Text] [PDF]

				B. Schroen, J. J. Leenders, A. van Erk, A. T. Bertrand, M. van Loon, R. E. van Leeuwen, N. Kubben, R. F. Duisters, M. W. Schellings, B. J. Janssen, et al. Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy J. Exp. Med., May 14, 2007; 204(5): 1227 - 1235. [Abstract] [Full Text] [PDF]

				C. Pilette, B. Colinet, R. Kiss, S. Andre, H. Kaltner, H-J. Gabius, M. Delos, J-P. Vaerman, M. Decramer, and Y. Sibille Increased galectin-3 expression and intra-epithelial neutrophils in small airways in severe COPD Eur. Respir. J., May 1, 2007; 29(5): 914 - 922. [Abstract] [Full Text] [PDF]

				R. R. van Kimmenade, J. L. Januzzi Jr, P. T. Ellinor, U. C. Sharma, J. A. Bakker, A. F. Low, A. Martinez, H. J. Crijns, C. A. MacRae, P. P. Menheere, et al. Utility of Amino-Terminal Pro-Brain Natriuretic Peptide, Galectin-3, and Apelin for the Evaluation of Patients With Acute Heart Failure J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1217 - 1224. [Abstract] [Full Text] [PDF]

				M. W.M. Schellings, M. Baumann, R. E.W. van Leeuwen, R. F.J.J. Duisters, S. H.P. Janssen, B. Schroen, C. J. Peutz-Kootstra, S. Heymans, and Y. M. Pinto Imatinib Attenuates End-Organ Damage in Hypertensive Homozygous TGR(mRen2)27 Rats Hypertension, March 1, 2006; 47(3): 467 - 474. [Abstract] [Full Text] [PDF]