Tumor necrosis factor triggers the expression and activation of matrix metalloproteinases through NADPH-dependent superoxide production

Tumor necrosis factor (TNF) is upregulated in a number of cardiomyopathies. This thesis investigates TNF in triggering the expression and activation of matrix metalloproteinases (MMPs) in pressure overload cardiac disease, and explores the role of superoxide. Cardiac pressure overload was generated in adult wild-type and TNF-/- mice by transverse aortic constriction. Isolated cardiomyocytes and cardiofibroblasts from neonatal mice ventricles were treated with recombinant TNF (rTNF), and MMP induction and activation were assessed, with and without apocynin (a NADPH-oxidase inhibitor). TNF-/- mice showed less superoxide production and MMP activation, compared to wild-type mice, following pressure overload. rTNF upregulated the production of NADPH-dependent superoxide in cardiomyocytes as early as 1 hour (24 hours in cardiofibroblasts). rTNF also increased the expression of MMP-9 and MMP-12 in cardiomyocytes more than in cardiofibroblasts, and MMP-8 and MMP-13 more in cardiofibroblasts. This induction in both cardiac cell types was concomitant with superoxide production.