title: Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?
abstract: BACKGROUND
  Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction.
  
  
  METHODS
  Healthy rats were daily ip injected with 20mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot.
  
  
  RESULTS
  After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression.
  
  
  CONCLUSIONS
  Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function.
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Deluyker
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Vesselina
authors.initials: V
authors.lastname: Ferferieva
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Noben
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Quirine
authors.initials: Q
authors.lastname: Swennen
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Bronckaers
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Ivo
authors.initials: I
authors.lastname: Lambrichts
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rigo
authors.affiliation: Biomedical Research Institute (BIOMED), Hasselt University, Martelarenlaan 42, BE 3500 Hasselt, Belgium. Electronic address: Virginie.Bito@uhasselt.be.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bito
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents / Q000378:metabolism* / Q000633:toxicity*; D017127:Glycation End Products, Advanced / Q000097:blood* / Q000633:toxicity*; D006331:Heart Diseases; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000097:blood* / Q000139:chemically induced* / Q000473:pathology
chemical_list: D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced
keywords: Echocardiography; Fibrosis; High molecular weight advanced glycation end products; RAGE