title: HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome.
abstract: OBJECTIVE
  The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties.
  
  
  RESULTS
  We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-β1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-β1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output).
  
  
  CONCLUSIONS
  In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.
authors.affiliation: Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique , Avenue Mounier 53 bte B1.53.09 à 1200 Brussels, Belgium.
authors.forename: Nerea
authors.initials: N
authors.lastname: Hermida
authors.forename: Andreas
authors.initials: A
authors.lastname: Markl
authors.forename: Julien
authors.initials: J
authors.lastname: Hamelet
authors.forename: Tim
authors.initials: T
authors.lastname: Van Assche
authors.forename: Annelies
authors.initials: A
authors.lastname: Vanderper
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Gauthier
authors.initials: G
authors.lastname: Noppe
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003971:Diastole; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D005464:Fluorobenzenes / Q000494:pharmacology*; D006331:Heart Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D011347:Procollagen / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D020127:Recovery of Function; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D055372:AMP-Activated Protein Kinases; D000199:Actins; D024042:Collagen Type I; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020738:Leptin; D011347:Procollagen; D011743:Pyrimidines; D011973:Receptors, LDL; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat; C543928:Prkaa2 protein, rat; C568305:Prkaa1 protein, rat
keywords: AMPK; Diastolic dysfunction; Metabolic syndrome; Myocardial fibrosis