title: Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload.
abstract: We have previously shown that genetic ablation of melusin, a muscle specific beta 1 integrin interacting protein, accelerates left ventricle (LV) dilation and heart failure in response to pressure overload. Here we show that melusin expression was increased during compensated cardiac hypertrophy in mice subjected to 1 week pressure overload, but returned to basal levels in LV that have undergone dilation after 12 weeks of pressure overload. To better understand the role of melusin in cardiac remodeling, we overexpressed melusin in heart of transgenic mice. Echocardiography analysis indicated that melusin over-expression induced a mild cardiac hypertrophy in basal conditions (30% increase in interventricular septum thickness) with no obvious structural and functional alterations. After prolonged pressure overload (12 weeks), melusin overexpressing hearts underwent further hypertrophy retaining concentric LV remodeling and full contractile function, whereas wild-type LV showed pronounced chamber dilation with an impaired contractility. Analysis of signaling pathways indicated that melusin overexpression induced increased basal phosphorylation of GSK3beta and ERK1/2. Moreover, AKT, GSK3beta and ERK1/2 were hyper-phosphorylated on pressure overload in melusin overexpressing compared with wild-type mice. In addition, after 12 weeks of pressure overload LV of melusin overexpressing mice showed a very low level of cardiomyocyte apoptosis and stromal tissue deposition, as well as increased capillary density compared with wild-type. These results demonstrate that melusin overexpression allows prolonged concentric compensatory hypertrophy and protects against the transition toward cardiac dilation and failure in response to long-standing pressure overload.
authors.affiliation: Department of Genetics, Biology, Turin University, Turin, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: De Acetis
authors.forename: Antonella
authors.initials: A
authors.lastname: Notte
authors.forename: Federica
authors.initials: F
authors.lastname: Accornero
authors.forename: Giulio
authors.initials: G
authors.lastname: Selvetella
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.forename: Mauro
authors.initials: M
authors.lastname: Sbroggiò
authors.forename: Federica
authors.initials: F
authors.lastname: Collino
authors.forename: Beniamina
authors.initials: B
authors.lastname: Pacchioni
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Lanfranchi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Aretini
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferretti
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000517:prevention & control*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling
chemical_list: D003598:Cytoskeletal Proteins; C122158:Itgb1bp2 protein, mouse; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3