title: Inverse relationship between raft LRP1 localization and non-raft ERK1,2/MMP9 activation in idiopathic dilated cardiomyopathy: potential impact in ventricular remodeling.
abstract: BACKGROUND
  Idiopathic dilated cardiomyopathy (IDCM) is characterized by adverse ventricular remodeling attributed to altered activity of extracellular matrix metalloproteinase (MMP). MMP overactivation is linked to changes in extracellular signal-regulated kinases (ERK), reportedly modulated by the low-density lipoprotein receptor-related protein 1 (LRP1) receptor. The aim of this work was to compare the levels, membrane distribution and interactions of LRP1, ERK1,2 and MMP2/9 in control and IDCM myocardium.
  
  
  METHODS
  Left ventricle samples from IDCM patients and control subjects were collected to analyze gene and protein expression by Real-time PCR and Western blot, respectively. Fractions enriched in cholesterol, Flotillin-1 and Caveolin-3 (rafts) were isolated from the remaining membrane (non-rafts) by sucrose gradient ultracentrifugation. We assessed the formation of LRP1-ERK1,2 complexes and MMP activity by immunoprecipitation and zymography, respectively.
  
  
  RESULTS
  In control myocardium, LRP1 was exclusively found in non-rafts while activation of ERK1,2 was preferentially detected in rafts. LRP1/p-ERK1,2 complexes were almost undetectable in rafts and non-rafts. In contrast, in IDCM myocardium, LRP1 moved to rafts and ERK1,2 activation was found in raft and non-raft fractions. Moreover, LRP1/p-ERK1,2 complexes were also found in both membrane fractions, although the amount was higher in non-rafts where MMP9 overactivation was exclusively detected.
  
  
  CONCLUSIONS
  The presented findings demonstrate a differential membrane compartmentalisation of ERK signaling in IDCM myocardium. The movement of LRP1 to rafts and the concomitant increase in non-raft-related ERK1,2/MMP9 activation may have crucial clinical implications in the progression of disease.
authors.affiliation: ICREC Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Roura
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain.
authors.forename: Roi
authors.initials: R
authors.lastname: Cal
authors.affiliation: ICREC Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gálvez-Montón
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Revuelta-Lopez
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Nasarre
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
authors.affiliation: ICREC Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain; Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Bayes-Genis
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain. Electronic address: cllorente@csic-iccc.org.
authors.forename: Vicenta
authors.initials: V
authors.lastname: Llorente-Cortés
mesh_terms: D000328:Adult; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000032:analysis* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: ERK; Idiopathic dilated cardiomyopathy; LRP1; Lipid rafts; MMP; Membrane compartmentalisation