title: Tumor necrosis factor receptor-associated factor 2 signaling provokes adverse cardiac remodeling in the adult mammalian heart.
abstract: BACKGROUND
  Tumor necrosis factor superfamily ligands provoke a dilated cardiac phenotype signal through a common scaffolding protein termed tumor necrosis factor receptor-associated factor 2 (TRAF2); however, virtually nothing is known about TRAF2 signaling in the adult mammalian heart.
  
  
  RESULTS
  We generated multiple founder lines of mice with cardiac-restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (myosin heavy chain [MHC]-TRAF2(HC)). MHC-TRAF2(HC) transgenic mice developed a time-dependent increase in cardiac hypertrophy, left ventricular dilation, and adverse left ventricular remodeling, and a significant decrease in LV+dP/dt and LV-dP/dt when compared with littermate controls (P<0.05 compared with littermate). During the early phases of left ventricular remodeling, there was a significant increase in total matrix metalloproteinase activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2(HC) mice aged, there was a significant decrease in total matrix metalloproteinase activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in nuclear factor-κB activation at 4 to 12 weeks and jun N-terminal kinases activation at 4 weeks in the MHC-TRAF2(HC) mice. Transciptional profiling revealed that >95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2(HC) hearts contained κB elements in their promoters.
  
  
  CONCLUSIONS
  These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.
authors.affiliation: Winters Center for Heart Failure Research Section of Cardiology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Divakaran
authors.forename: Sarah
authors.initials: S
authors.lastname: Evans
authors.forename: Veli K
authors.initials: VK
authors.lastname: Topkara
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Jana
authors.initials: J
authors.lastname: Burchfield
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Jianwen
authors.initials: J
authors.lastname: Dong
authors.forename: Huei-Ping
authors.initials: HP
authors.lastname: Tzeng
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Philip M
authors.initials: PM
authors.lastname: Barger
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D020869:Gene Expression Profiling; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D032342:Muscle Cells / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2
keywords: TNF receptor–associated factor 2; dilated cardiomyopathy; inflammation; tumor necrosis factor superfamily