title: Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.
abstract: BACKGROUND
  Galectin-3 has been implicated in the development of organ fibrosis. It is unknown whether it is a relevant therapeutic target in cardiac remodeling and heart failure.
  
  
  RESULTS
  Galectin-3 knock-out and wild-type mice were subjected to angiotensin II infusion (2.5 µg/kg for 14 days) or transverse aortic constriction for 28 days to provoke cardiac remodeling. The efficacy of the galectin-3 inhibitor N-acetyllactosamine was evaluated in TGR(mREN2)27 (REN2) rats and in wild-type mice with the aim of reversing established cardiac remodeling after transverse aortic constriction. In wild-type mice, angiotensin II and transverse aortic constriction perturbations caused left-ventricular (LV) hypertrophy, decreased fractional shortening, and increased LV end-diastolic pressure and fibrosis (P<0.05 versus control wild type). Galectin-3 knock-out mice also developed LV hypertrophy but without LV dysfunction and fibrosis (P=NS). In REN2 rats, pharmacological inhibition of galectin-3 attenuated LV dysfunction and fibrosis. To elucidate the beneficial effects of galectin-3 inhibition on myocardial fibrogenesis, cultured fibroblasts were treated with galectin-3 in the absence or presence of galectin-3 inhibitor. Inhibition of galectin-3 was associated with a downregulation in collagen production (collagen I and III), collagen processing, cleavage, cross-linking, and deposition. Similar results were observed in REN2 rats. Inhibition of galectin-3 also attenuated the progression of cardiac remodeling in a long-term transverse aortic constriction mouse model.
  
  
  CONCLUSIONS
  Genetic disruption and pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development. Drugs binding to galectin-3 may be potential therapeutic candidates for the prevention or reversal of heart failure with extensive fibrosis.
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Lili
authors.initials: L
authors.lastname: Yu
authors.forename: Willem P T
authors.initials: WP
authors.lastname: Ruifrok
authors.forename: Maxi
authors.initials: M
authors.lastname: Meissner
authors.forename: Eelke M
authors.initials: EM
authors.lastname: Bos
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Bahram
authors.initials: B
authors.lastname: Sanjabi
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Goldstein
authors.forename: Jasper A
authors.initials: JA
authors.lastname: Koerts
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
mesh_terms: D000606:Amino Sugars / Q000627:therapeutic use*; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020257:Ventricular Remodeling
chemical_list: D000606:Amino Sugars; D024042:Collagen Type I; D037502:Galectin 3; C000458:N-acetyllactosamine; D004247:DNA