Galectin-3, Cardiac Function, and Fibrosis
2016; Elsevier BV; Volume: 186; Issue: 8 Linguagem: Inglês
10.1016/j.ajpath.2016.05.002
ISSN1525-2191
AutoresWouter C. Meijers, Natalia López‐Andrés, Rudolf A. de Boer,
Tópico(s)Peptidase Inhibition and Analysis
ResumoWe read with interest the article by Frunza et al1Frunza O. Russo I. Saxena A. Shinde A.V. Humeres C. Hanif W. Rai V. Su Y. Frangogiannis N.G. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis.Am J Pathol. 2016; 186: 1103-1127Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar in The American Journal of Pathology. In this article, the authors studied the expression of galectin-3 (Gal-3) in the well-established transverse aortic constriction (TAC) mouse model. In wild-type (WT) mice, cardiac Gal-3 was shown to be markedly up-regulated, and the level of Gal-3 expression was associated with the severity of adverse cardiac remodeling. Frunza et al1Frunza O. Russo I. Saxena A. Shinde A.V. Humeres C. Hanif W. Rai V. Su Y. Frangogiannis N.G. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis.Am J Pathol. 2016; 186: 1103-1127Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar also studied mice deficient for Gal-3 (Gal-3 KO mice). Previously, Gal-3 KO mice have extensively been studied by our group and by others, and it has consistently been reported that Gal-3 KO mice are protected from fibrosis formation in response to profibrotic perturbations, including the heart,2Yu L. Ruifrok W.P. Meissner M. Bos E.M. van Goor H. Sanjabi B. van der Harst P. Pitt B. Goldstein I.J. Koerts J.A. van Veldhuisen D.J. Bank R.A. van Gilst W.H. Sillje H.H. de Boer R.A. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.Circ Heart Fail. 2013; 6: 107-117Crossref PubMed Scopus (329) Google Scholar, 3Pineda M.A. Cuervo H. Fresno M. Soto M. Bonay P. Lack of galectin-3 prevents cardiac fibrosis and effective immune responses in a murine model of Trypanosoma cruzi infection.J Infect Dis. 2015; 212: 1160-1171Crossref PubMed Scopus (35) Google Scholar, 4Calvier L. Martinez-Martinez E. Miana M. Cachofeiro V. Rousseau E. Sadaba J.R. Zannad F. Rossignol P. Lopez-Andres N. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.JACC Heart Fail. 2015; 3: 59-67Crossref PubMed Scopus (147) Google Scholar, 5Martinez-Martinez E. Calvier L. Fernandez-Celis A. Rousseau E. Jurado-Lopez R. Rossoni L.V. Jaisser F. Zannad F. Rossignol P. Cachofeiro V. Lopez-Andres N. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.Hypertension. 2015; 66: 767-775Crossref PubMed Scopus (104) Google Scholar, 6Gonzalez G.E. Cassaglia P. Noli Truant S. Fernandez M.M. Wilensky L. Volberg V. Malchiodi E.L. Morales C. Gelpi R.J. Galectin-3 is essential for early wound healing and ventricular remodeling after myocardial infarction in mice.Int J Cardiol. 2014; 176: 1423-1425Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar kidney,4Calvier L. Martinez-Martinez E. Miana M. Cachofeiro V. Rousseau E. Sadaba J.R. Zannad F. Rossignol P. Lopez-Andres N. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.JACC Heart Fail. 2015; 3: 59-67Crossref PubMed Scopus (147) Google Scholar, 7Fernandes Bertocchi A.P. Campanhole G. Wang P.H. Goncalves G.M. Damiao M.J. Cenedeze M.A. Beraldo F.C. de Paula Antunes Teixeira V. Dos Reis M.A. Mazzali M. Pacheco-Silva A. Camara N.O. A role for galectin-3 in renal tissue damage triggered by ischemia and reperfusion injury.Transpl Int. 2008; 21: 999-1007Crossref PubMed Scopus (65) Google Scholar, 8Iacobini C. Oddi G. Menini S. Amadio L. Ricci C. Di Pippo C. Sorcini M. Pricci F. Pugliese F. Pugliese G. Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice.Am J Physiol Renal Physiol. 2005; 289: F611-F621Crossref PubMed Scopus (50) Google Scholar, 9Iacobini C. Menini S. Oddi G. Ricci C. Amadio L. Pricci F. Olivieri A. Sorcini M. Di Mario U. Pesce C. Pugliese G. Galectin-3/AGE-receptor 3 knockout mice show accelerated AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor.FASEB J. 2004; 18: 1773-1775Crossref PubMed Scopus (95) Google Scholar, 10Henderson N.C. Mackinnon A.C. Farnworth S.L. Kipari T. Haslett C. Iredale J.P. Liu F.T. Hughes J. Sethi T. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis.Am J Pathol. 2008; 172: 288-298Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar liver,11Henderson N.C. Mackinnon A.C. Farnworth S.L. Poirier F. Russo F.P. Iredale J.P. Haslett C. Simpson K.J. Sethi T. Galectin-3 regulates myofibroblast activation and hepatic fibrosis.Proc Natl Acad Sci U S A. 2006; 103: 5060-5065Crossref PubMed Scopus (465) Google Scholar blood vessels,12Calvier L. Miana M. Reboul P. Cachofeiro V. Martinez-Martinez E. de Boer R.A. Poirier F. Lacolley P. Zannad F. Rossignol P. Lopez-Andres N. Galectin-3 mediates aldosterone-induced vascular fibrosis.Arterioscler Thromb Vasc Biol. 2013; 33: 67-75Crossref PubMed Scopus (264) Google Scholar and lung13Ge X.N. Bahaie N.S. Kang B.N. Hosseinkhani M.R. Ha S.G. Frenzel E.M. Liu F.T. Rao S.P. Sriramarao P. Allergen-induced airway remodeling is impaired in galectin-3-deficient mice.J Immunol. 2010; 185: 1205-1214Crossref PubMed Scopus (72) Google Scholar, 14Mackinnon A.C. Gibbons M.A. Farnworth S.L. Leffler H. Nilsson U.J. Delaine T. Simpson A.J. Forbes S.J. Hirani N. Gauldie J. Sethi T. Regulation of transforming growth factor-beta1-driven lung fibrosis by galectin-3.Am J Respir Crit Care Med. 2012; 185: 537-546Crossref PubMed Scopus (345) Google Scholar (Table 1). In contrast to these studies, Frunza et al1Frunza O. Russo I. Saxena A. Shinde A.V. Humeres C. Hanif W. Rai V. Su Y. Frangogiannis N.G. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis.Am J Pathol. 2016; 186: 1103-1127Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar report that Gal-3 KO mice develop cardiac fibrosis; the reasons for this discrepant result warrant further study.Table 1Overview of Studies with Galectin-3 KO MiceStudyModelMain findingsCardiac Yu et al2Yu L. Ruifrok W.P. Meissner M. Bos E.M. van Goor H. Sanjabi B. van der Harst P. Pitt B. Goldstein I.J. Koerts J.A. van Veldhuisen D.J. Bank R.A. van Gilst W.H. Sillje H.H. de Boer R.A. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.Circ Heart Fail. 2013; 6: 107-117Crossref PubMed Scopus (329) Google ScholarTAC (pressure overload)Less fibrosisPreservation of LV function Yu et al2Yu L. Ruifrok W.P. Meissner M. Bos E.M. van Goor H. Sanjabi B. van der Harst P. Pitt B. Goldstein I.J. Koerts J.A. van Veldhuisen D.J. Bank R.A. van Gilst W.H. Sillje H.H. de Boer R.A. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.Circ Heart Fail. 2013; 6: 107-117Crossref PubMed Scopus (329) Google ScholarAngiotensin II infusionLess fibrosisPreservation of LV function Pineda et al3Pineda M.A. Cuervo H. Fresno M. Soto M. Bonay P. Lack of galectin-3 prevents cardiac fibrosis and effective immune responses in a murine model of Trypanosoma cruzi infection.J Infect Dis. 2015; 212: 1160-1171Crossref PubMed Scopus (35) Google ScholarInfection with Trypanosoma cruzi (Chagas)No fibrotic content Calvier et al4Calvier L. Martinez-Martinez E. Miana M. Cachofeiro V. Rousseau E. Sadaba J.R. Zannad F. Rossignol P. Lopez-Andres N. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.JACC Heart Fail. 2015; 3: 59-67Crossref PubMed Scopus (147) Google ScholarAldosterone infusionResistant against aldosterone effects (remodeling) Martinez-Martinez et al5Martinez-Martinez E. Calvier L. Fernandez-Celis A. Rousseau E. Jurado-Lopez R. Rossoni L.V. Jaisser F. Zannad F. Rossignol P. Cachofeiro V. Lopez-Andres N. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.Hypertension. 2015; 66: 767-775Crossref PubMed Scopus (104) Google ScholarAldosterone infusionResistant to cardiac inflammation Gonzalez et al6Gonzalez G.E. Cassaglia P. Noli Truant S. Fernandez M.M. Wilensky L. Volberg V. Malchiodi E.L. Morales C. Gelpi R.J. Galectin-3 is essential for early wound healing and ventricular remodeling after myocardial infarction in mice.Int J Cardiol. 2014; 176: 1423-1425Abstract Full Text Full Text PDF PubMed Scopus (47) Google ScholarMyocardial infarctionLess fibrosisLarger infarct sizeRenal Calvier et al4Calvier L. Martinez-Martinez E. Miana M. Cachofeiro V. Rousseau E. Sadaba J.R. Zannad F. Rossignol P. Lopez-Andres N. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.JACC Heart Fail. 2015; 3: 59-67Crossref PubMed Scopus (147) Google ScholarAldosterone infusionLess perivascular fibrosis Fernandes Bertocchi et al7Fernandes Bertocchi A.P. Campanhole G. Wang P.H. Goncalves G.M. Damiao M.J. Cenedeze M.A. Beraldo F.C. de Paula Antunes Teixeira V. Dos Reis M.A. Mazzali M. Pacheco-Silva A. Camara N.O. A role for galectin-3 in renal tissue damage triggered by ischemia and reperfusion injury.Transpl Int. 2008; 21: 999-1007Crossref PubMed Scopus (65) Google Scholar45 Minutes of renal pedicle occlusionLess acute tubular necrosisMore prominent tubular regeneration Iacobini et al8Iacobini C. Oddi G. Menini S. Amadio L. Ricci C. Di Pippo C. Sorcini M. Pricci F. Pugliese F. Pugliese G. Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice.Am J Physiol Renal Physiol. 2005; 289: F611-F621Crossref PubMed Scopus (50) Google ScholarAgingAge-dependent increases in proteinuria, albuminuria, and glomerular sclerosis Iacobini et al9Iacobini C. Menini S. Oddi G. Ricci C. Amadio L. Pricci F. Olivieri A. Sorcini M. Di Mario U. Pesce C. Pugliese G. Galectin-3/AGE-receptor 3 knockout mice show accelerated AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor.FASEB J. 2004; 18: 1773-1775Crossref PubMed Scopus (95) Google ScholarN-carboxymethyllysine injectionHigher circulating and renal AGE levelsRenal dysfunction and structural changes Henderson et al10Henderson N.C. Mackinnon A.C. Farnworth S.L. Kipari T. Haslett C. Iredale J.P. Liu F.T. Hughes J. Sethi T. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis.Am J Pathol. 2008; 172: 288-298Abstract Full Text Full Text PDF PubMed Scopus (411) Google ScholarUnilateral ureteric obstructionComparable macrophage recruitmentLess myofibroblast accumulation/activationLess fibrosisLiver Henderson et al11Henderson N.C. Mackinnon A.C. Farnworth S.L. Poirier F. Russo F.P. Iredale J.P. Haslett C. Simpson K.J. Sethi T. Galectin-3 regulates myofibroblast activation and hepatic fibrosis.Proc Natl Acad Sci U S A. 2006; 103: 5060-5065Crossref PubMed Scopus (465) Google ScholarCarbon tetrachloride–induced liver injuryLess fibrosisLung Ge et al13Ge X.N. Bahaie N.S. Kang B.N. Hosseinkhani M.R. Ha S.G. Frenzel E.M. Liu F.T. Rao S.P. Sriramarao P. Allergen-induced airway remodeling is impaired in galectin-3-deficient mice.J Immunol. 2010; 185: 1205-1214Crossref PubMed Scopus (72) Google ScholarRepetitive allergen challengeLess remodeling of the airways with reduced mucus secretion, fibrosis, smooth muscle thickness, and angiogenesis Mackinnon et al14Mackinnon A.C. Gibbons M.A. Farnworth S.L. Leffler H. Nilsson U.J. Delaine T. Simpson A.J. Forbes S.J. Hirani N. Gauldie J. Sethi T. Regulation of transforming growth factor-beta1-driven lung fibrosis by galectin-3.Am J Respir Crit Care Med. 2012; 185: 537-546Crossref PubMed Scopus (345) Google ScholarBleomycin-induced lung injuryLess lung fibrosis, reduced TGF-β– induced EMT, and myofibroblast activationVascular Calvier et al12Calvier L. Miana M. Reboul P. Cachofeiro V. Martinez-Martinez E. de Boer R.A. Poirier F. Lacolley P. Zannad F. Rossignol P. Lopez-Andres N. Galectin-3 mediates aldosterone-induced vascular fibrosis.Arterioscler Thromb Vasc Biol. 2013; 33: 67-75Crossref PubMed Scopus (264) Google ScholarAldosterone infusion (6 hours and 3 weeks)Less inflammationLess collagen type I deposition(Both short- and long-term)AGE, advanced glycation end product; EMT, epithelial-mesenchymal transition; galectin-3 KO, mice deficient for galectin-3; LV, left ventricular; TAC, transverse aortic constriction; TGF-β, transforming growth factor-β. Open table in a new tab AGE, advanced glycation end product; EMT, epithelial-mesenchymal transition; galectin-3 KO, mice deficient for galectin-3; LV, left ventricular; TAC, transverse aortic constriction; TGF-β, transforming growth factor-β. Furthermore, the authors report that Gal-3 has no role in the development of left ventricular (LV) dysfunction. However, when looking into their results on contractile function, we do not reach the same conclusion. Specifically, the results for LV function are reported as percentage change in left ventricular ejection fraction (LVEF). We assumed a normal LVEF in control mice of 80%. Looking at the results, we then calculated that after 28 days of TAC, LVEF in the Frunza study was decreased by approximately 8% in WT mice (from approximately 80% to approximately 74%), but only by approximately 1% in Gal-3 KO mice (from approximately 80% to approximately 79%). Furthermore, LVEF was decreased in (male) WT mice by approximately 18% (from approximately 80% to approximately 64%), whereas it was actually improved by approximately 2% in (male) Gal-3 KO mice (from approximately 80% to approximately 82%). After 56 days of TAC, LVEF was decreased by approximately 10% in male WT mice (from approximately 80% to approximately 72%), whereas it was improved by 3% in male Gal-3 KO mice (from approximately 80% to approximately 83%). LV volumes were reported to be numerically larger in WT mice compared to Gal-3 KO mice. The results for females were mostly neutral, although chamber dilatation also appeared delayed in Gal-3 KO mice. The authors interpret their findings on LV function as neutral because there were no statistically significant differences, and explain these disparate findings by pointing toward sex differences. But we do not agree that the data are disparate. The main issue is to know what the a priori hypothesis regarding LV remodeling was; in other words, what percentage change in LVEF was considered relevant by the authors? Differences in LVEF up to 20% are considered irrelevant by Frunza et al,1Frunza O. Russo I. Saxena A. Shinde A.V. Humeres C. Hanif W. Rai V. Su Y. Frangogiannis N.G. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis.Am J Pathol. 2016; 186: 1103-1127Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar but from a clinical perspective, 10% or even a 5% change in LVEF is highly relevant, and the reported average outcomes unequivocally point toward a substantial improvement in LVEF in Gal-3 KO mice. It has been proposed that the effect size is the most important parameter to consider, not the P value (American Statistical Association, https://www.amstat.org/newsroom/pressreleases/P-ValueStatement.pdf, last accessed April 17, 2016). We have reported2Yu L. Ruifrok W.P. Meissner M. Bos E.M. van Goor H. Sanjabi B. van der Harst P. Pitt B. Goldstein I.J. Koerts J.A. van Veldhuisen D.J. Bank R.A. van Gilst W.H. Sillje H.H. de Boer R.A. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.Circ Heart Fail. 2013; 6: 107-117Crossref PubMed Scopus (329) Google Scholar exactly the same results regarding contractile function, so that these results by Frunza et al1Frunza O. Russo I. Saxena A. Shinde A.V. Humeres C. Hanif W. Rai V. Su Y. Frangogiannis N.G. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis.Am J Pathol. 2016; 186: 1103-1127Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar and ours regarding myocardial contractile function after TAC are in fact completely compatible. The preservation of LVEF in Gal-3 KO mice underlines the notion that Gal-3 may be an amenable factor in heart failure and myocardial fibrosis.15de Boer R.A. van der Velde A.R. Mueller C. van Veldhuisen D.J. Anker S.D. Peacock W.F. Adams K.F. Maisel A. Galectin-3: a modifiable risk factor in heart failure.Cardiovasc Drugs Ther. 2014; 28: 237-246Crossref PubMed Scopus (54) Google Scholar But before embarking on further studies, future work is needed to describe the exact dynamics of Gal-3 expression. The results of Frunza et al1Frunza O. Russo I. Saxena A. Shinde A.V. Humeres C. Hanif W. Rai V. Su Y. Frangogiannis N.G. Myocardial galectin-3 expression is associated with remodeling of the pressure-overloaded heart and may delay the hypertrophic response without affecting survival, dysfunction, and cardiac fibrosis.Am J Pathol. 2016; 186: 1103-1127Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar provide important novel data to this aim. Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure-Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac FibrosisThe American Journal of PathologyVol. 186Issue 5PreviewThe β-galactoside–binding animal lectin galectin-3 is predominantly expressed by activated macrophages and is a promising biomarker for patients with heart failure. Galectin-3 regulates inflammatory and fibrotic responses; however, its role in cardiac remodeling remains unclear. We hypothesized that galectin-3 may be up-regulated in the pressure-overloaded myocardium and regulate hypertrophy and fibrosis. In normal mouse myocardium, galectin-3 was constitutively expressed in macrophages and was localized in atrial but not ventricular cardiomyocytes. Full-Text PDF Open ArchiveAuthors' ReplyThe American Journal of PathologyVol. 186Issue 8PreviewThis correspondence is a reply to Galectin-3, Cardiac Function, and Fibrosis by Wouter C. Meijers et al. Full-Text PDF Open Archive
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