TNF-α increases cardiac fibroblast lysyl oxidase expression through TGF-β and PI3Kinase signaling pathways

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.