title: Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction.
abstract: OBJECTIVE
  Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach.
  
  
  RESULTS
  Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility.
  
  
  CONCLUSIONS
  Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.
authors.affiliation: Department of Cardiology, University of Göttingen, Heart Research Center Göttingen, Göttingen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Unsöld
authors.forename: Axel
authors.initials: A
authors.lastname: Kaul
authors.forename: Mauro
authors.initials: M
authors.lastname: Sbroggiò
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Marc
authors.initials: M
authors.lastname: Van Bilsen
authors.forename: Chantal
authors.initials: C
authors.lastname: Munts
authors.forename: Karin
authors.initials: K
authors.lastname: Sipido
authors.forename: Virginie
authors.initials: V
authors.lastname: Bito
authors.forename: Elke
authors.initials: E
authors.lastname: Detre
authors.forename: Nana Maria
authors.initials: NM
authors.lastname: Wagner
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
authors.forename: Tim
authors.initials: T
authors.lastname: Seidler
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogt
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Balligand
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouzin
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuß
mesh_terms: D000818:Animals; D017209:Apoptosis; D003094:Collagen / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D056966:Excitation Contraction Coupling; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D006341:Heart Rupture / Q000209:etiology / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism*; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D006360:Heat-Shock Proteins; C122158:Itgb1bp2 protein, mouse; D009124:Muscle Proteins; D003094:Collagen
keywords: Chaperon; Infarction; Map kinase; Remodelling; Transgenic animal models