title: Targeted overexpression of noncleavable and secreted forms of tumor necrosis factor provokes disparate cardiac phenotypes.
abstract: BACKGROUND
  Recent studies suggest that posttranslation processing or "shedding" (ie, secretion) of tumor necrosis factor (TNF) by tumor necrosis factor-alpha converting enzyme (TACE) may contribute to the left ventricular (LV) remodeling that occurs in the failing human heart.
  
  
  RESULTS
  To address the functional significance of TNF shedding, we generated lines of transgenic mice with targeted overexpression of secreted wild-type (MHCsTNF2) TNF and overexpression of a mutated noncleavable transmembrane form of TNF (MHCmTNF). Both lines of mice had overlapping levels of myocardial TNF protein; however, the phenotypes of the MHCsTNF2 and MHCmTNF mice were strikingly disparate. Whereas the MHCmTNF mice developed a concentric LV hypertrophy phenotype, the MHCsTNF2 mice developed a dilated LV phenotype. The fibrillar collagen weave in MHCmTNF mice with concentric hypertrophy was characterized by thick collagen fibrils and increased collagen content, whereas the fibrillar collagen weave in the MHCsTNF2 mice with LV dilation was characterized by a diminished collagen content. Inhibition of matrix metalloproteinases with a broad-based matrix metalloproteinase inhibitor prevented LV dilation in the MHCsTNF2 mice.
  
  
  CONCLUSIONS
  These findings suggest that posttranslational processing of TNF, as opposed to TNF expression per se, is responsible for the adverse cardiac remodeling that occurs after sustained TNF overexpression.
authors.affiliation: Winters Center for Heart Failure Research, Houston VAMC, Baylor College of Medicine and the Methodist Hospital, Houston, Tex 77030, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Ziad
authors.initials: Z
authors.lastname: Dibbs
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nemoto
authors.forename: Gilberto
authors.initials: G
authors.lastname: DeFreitas
authors.forename: Blase A
authors.initials: BA
authors.lastname: Carabello
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wilson
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000818:Animals; D024022:Fibrillar Collagens / Q000032:analysis; D005786:Gene Expression Regulation; D018390:Gene Targeting; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D024022:Fibrillar Collagens; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases