title: Mechanisms of novel cardioprotective functions of CCN2/CTGF in myocardial ischemia-reperfusion injury.
abstract: CCN2/connective tissue growth factor (CTGF), a CCN family matricellular protein repressed in healthy hearts after birth, is induced in heart failure of various etiologies. Multiple cellular and biological functions have been assigned to CCN2/CTGF depending on cellular context. However, the functions and mechanisms of action of CCN2/CTGF in the heart as well as its roles in cardiac physiology and pathophysiology remain unknown. Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were generated and compared with nontransgenic littermate control (NLC) mice. Tg-CTGF mice displayed slightly lower cardiac mass and inconspicuous increase of myocardial collagen compared with NLC mice but no evidence of contractile dysfunction. Analysis of the myocardial transcriptome by DNA microarray revealed activation of several distinct gene programs in Tg-CTGF hearts involved in cardioprotection and growth inhibition. Indeed, Tg-CTGF mice subjected to ischemia-reperfusion injury by in situ transient occlusion of the left anterior descending coronary artery in vivo displayed reduced vulnerability with markedly diminished infarct size. These findings were recapitulated in isolated hearts perfused with recombinant human (h)CTGF before the ischemia-reperfusion procedure. Consistently, Tg-CTGF hearts, as well as isolated adult cardiac myocytes exposed to recombinant hCTGF, displayed enhanced phosphorylation and activity of the Akt/p70S6 kinase/GSK-3β salvage kinase pathway and induction of several genes with reported cardioprotective functions. Inhibition of Akt activities also prevented the cardioprotective phenotype of hearts from Tg-CTGF mice. This report provides novel evidence that CTGF confers cardioprotection by salvage phosphokinase signaling leading to inhibition of GSK-3β activities, activation of phospho-SMAD2, and reprogramming of gene expression.
authors.affiliation: Institute for Surgical Research, Department of Cardiology, Center for Heart Failure Research, Oslo University Hospital-Rikshospitalet, University of Oslo, Norway.
authors.forename: M Shakil
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Jørgen
authors.initials: J
authors.lastname: Gravning
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Martinov
authors.forename: Thomas G
authors.initials: TG
authors.lastname: von Lueder
authors.forename: Thor
authors.initials: T
authors.lastname: Edvardsen
authors.forename: Gabor
authors.initials: G
authors.lastname: Czibik
authors.forename: Ingvild T
authors.initials: IT
authors.lastname: Moe
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vinge
authors.forename: Erik
authors.initials: E
authors.lastname: Øie
authors.forename: Guro
authors.initials: G
authors.lastname: Valen
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000494:pharmacology*; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism
chemical_list: C526318:CCN2 protein, mouse; D002316:Cardiotonic Agents; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D055513:Connective Tissue Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3