title: Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction.
abstract: OBJECTIVE
  This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI).
  
  
  BACKGROUND
  The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood.
  
  
  METHODS
  MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-β and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined.
  
  
  RESULTS
  In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected.
  
  
  CONCLUSIONS
  MRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling.
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain; Department of Internal Medicine, School of Medicine, University of Murcia, Murcia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lax
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain; Department of Internal Medicine, School of Medicine, University of Murcia, Murcia, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Sanchez-Mas
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain; Department of Internal Medicine, School of Medicine, University of Murcia, Murcia, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Asensio-Lopez
authors.affiliation: Veterinary Teaching Hospital, Department of Veterinary Medicine and Surgery, University of Murcia, Murcia, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Fernandez-Del Palacio
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Caballero
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Iris P
authors.initials: IP
authors.lastname: Garrido
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Pastor-Perez
authors.affiliation: Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.affiliation: Cardiology Department, University Hospital Virgen de la Arrixaca, Murcia, Spain; Department of Internal Medicine, School of Medicine, University of Murcia, Murcia, Spain. Electronic address: dpascual@um.es.
authors.forename: Domingo A
authors.initials: DA
authors.lastname: Pascual-Figal
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D037502:Galectin 3 / Q000494:pharmacology*; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D012313:RNA / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013599:Systole; D015854:Up-Regulation / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D020257:Ventricular Remodeling
chemical_list: D037502:Galectin 3; C553108:Il33 protein, rat; D000067596:Interleukin-33; D007378:Interleukins; D000451:Mineralocorticoid Receptor Antagonists; D017472:Receptors, Interleukin-1; C000589812:ST2 protein, rat; D012313:RNA
keywords: eplerenone; heart failure; myocardial infarction; remodeling; spironolactone