title: TNF-α increases cardiac fibroblast lysyl oxidase expression through TGF-β and PI3Kinase signaling pathways.
abstract: TNF-α is a proinflammatory cytokine that is upregulated in many cardiac diseases. The increase of TNF-α expression affects both heart function and the structure of the extracellular matrix. Lysyl oxidase (LOX) is a key enzyme responsible for the maturation of extracellular matrix proteins, including collagens type I and III. In this study, we investigated the regulation of LOX expression and activity by TNF-α using adult rat cardiac fibroblasts. Our results indicate that TNF-α has a dichotomous effect on LOX expression by cardiac fibroblasts. Low dose TNF-α (1-5 ng/ml) decreased LOX expression, whereas higher doses (10-30 ng/ml) increased expression. The higher dose TNF-α effect on LOX expression was attenuated by the inhibition of PI3Kinase/Akt pathway. TGF-β1 signaling played a significant role in mediating the TNF-α effect. TNF-α increased the expression of TGF-β, and TGF-β receptors type I and II, and also stimulated Smad3 phosphorylation. Inhibition of TGF-β receptor I or Smad3 prevented increased LOX expression by TNF-α. These findings indicate that TNF-α stimulated LOX expression may play an important role in progressive cardiac fibrosis.
authors: Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
authors: Tetyana G
authors: TG
authors: Voloshenyuk
authors: Andrew D
authors: AD
authors: Hart
authors: Elena
authors: E
authors: Khoutorova
authors: Jason D
authors: JD
authors: Gardner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D008249:Protein-Lysine 6-Oxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt