title: Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor.
abstract: BACKGROUND
  The mechanisms responsible for tumor necrosis factor (TNF)-induced LV structural remodeling in the adult heart are not known.
  
  
  RESULTS
  We generated a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF that develop progressive LV dilation/remodeling from 4 to 12 weeks of age. During the early phases of LV structural remodeling, there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded to a decrease in total myocardial fibrillar collagen content. As the MHCsTNF mice aged, there was a significant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP activity and myocardial fibrillar collagen content were related to a time- dependent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)-1 levels, resulting in a significant time-dependent decrease in the MMP activity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechanism for the increase in myocardial fibrosis, we also measured levels of TGF-beta(1) and TGF-beta(2) protein levels, which were shown to be significantly elevated in the hearts of the MHCsTNF mice.
  
  
  CONCLUSIONS
  Our results suggest that progressive time-dependent changes in the balance between MMP activity and TIMP activity are responsible, at least in part, for the spectrum of TNF-induced changes in the myofibrillar collagen content that occur during LV structural remodeling in the MHCsTNF mice.
authors.affiliation: Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Affairs Medical Center, Houston, TX 77030, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: M L
authors.initials: ML
authors.lastname: Coker
authors.forename: K M
authors.initials: KM
authors.lastname: Kurrelmeyer
authors.forename: W R
authors.initials: WR
authors.lastname: MacLellan
authors.forename: F J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: F G
authors.initials: FG
authors.lastname: Spinale
authors.forename: D L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009210:Myofibrils / Q000378:metabolism / Q000648:ultrastructure; D009928:Organ Specificity / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D020782:Matrix Metalloproteinases