title: Targeted overexpression of transmembrane tumor necrosis factor provokes a concentric cardiac hypertrophic phenotype.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) is initially synthesized as a 26-kDa transmembrane protein that is enzymatically cleaved by TNF-alpha converting enzyme (TACE) to generate a 17-kDa form of "secreted" TNF. Whereas the effects of secreted TNF in the heart have been characterized extensively, the effects of transmembrane TNF in the heart are unknown.
  
  
  RESULTS
  We generated lines of transgenic mice with cardiac-restricted overexpression of a noncleavable, transmembrane form of TNF. We next treated a previously generated transgenic line of mice with cardiac-restricted expression of cleavable TNF (referred to as MHCsTNF mice) with a TACE inhibitor (DPC-IDR1) to determine whether TACE inhibition would prevent the transition from concentric hypertrophy to left ventricular (LV) dilation that occurs in this line of transgenic mice. Two of the founder lines did not have a demonstrable phenotype (M-41 and M-45), whereas a third line developed a concentric hypertrophic cardiac phenotype (M-48). Characterization of the M-48 line at 6 weeks of age showed that this line developed concentric hypertrophy, with an increase in myocyte cross-sectional area and reexpression of the fetal gene program. Four weeks of TACE inhibition abrogated the LV dilation in the MHCsTNF mice and resulted in an increase in LV wall thickness and increased myocyte cross-sectional area, thus mimicking the effects observed in the mice with noncleavable, transmembrane TNF.
  
  
  CONCLUSIONS
  These studies show that transmembrane TNF is biologically active and provokes a concentric hypertrophic cardiac phenotype, thus suggesting that posttranslational processing (ie, secretion) of TNF is responsible for the dilated cardiomyopathic phenotype in mice with targeted, cardiac-restricted overexpression of TNF.
authors.affiliation: Winters Center for Heart Failure Research, Houston, TX 77030, USA.
authors.forename: Ziad I
authors.initials: ZI
authors.lastname: Dibbs
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nemoto
authors.forename: Gilberto
authors.initials: G
authors.lastname: DeFreitas
authors.forename: Maha
authors.initials: M
authors.lastname: Abdellatif
authors.forename: Blase A
authors.initials: BA
authors.lastname: Carabello
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Giora
authors.initials: G
authors.lastname: Feuerstein
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D030801:Animals, Genetically Modified; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002415:Cats; D002462:Cell Membrane / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting / Q000379:methods*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse