title: TNF-like weak inducer of apoptosis aggravates left ventricular dysfunction after myocardial infarction in mice.
abstract: BACKGROUND
  TNF-like weak inducer of apoptosis (TWEAK) has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known.
  
  
  OBJECTIVE
  To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice.
  
  
  RESULTS
  TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS) in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14-/- mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14+/+). Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival.
  
  
  CONCLUSIONS
  TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α.
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Jarr
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Sabine
authors.identifier: 0000-0002-2284-2810
authors.initials: S
authors.lastname: Eschricht
authors.affiliation: Department of Immunology, Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.identifier: 0000-0001-5283-1939
authors.initials: M
authors.lastname: Preusch
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology and Angiology, University of Kiel, Schittenhelmstraße 12, 24105 Kiel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Emmanuel
authors.identifier: 0000-0002-2412-3668
authors.initials: E
authors.lastname: Chorianopoulos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000074049:Cytokine TWEAK; D004452:Echocardiography; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010085:Oxidative Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
chemical_list: D000074049:Cytokine TWEAK; D011994:Recombinant Proteins; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors