Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy

Myocardial fibrosis caused by maladaptive extracellular matrix (ECM) remode ling is implicated in the dysfunction of the failing heart. Matrix metallop roteinases (MMPs) regulate ECM remodeling, and are regulated by cytokines. Transgenic mice with cardiac-specific overexpression of tumor necrosis fact or alpha (TNF-alpha) (TNF1.6) develop heart failure. We hypothesized that m odulation of TNF-alpha and/or MMP activity might alter the myocardial ECM r emodeling process and the development of heart failure. To test this hypoth esis, we took advantage of the TNF1.6 mice and studied soluble and total co llagens and collagen type profiling by using hydroxyproline quantification, Sircol collagen assay, Northern blot analysis, and immunohistochemistry an d studied myocardial function by using echocardiography. Progressive ventri cular hypertrophy and dilation in the TNF1.6 mice were accompanied by a sig nificant increase in MMP-2 and MMP-9 activity, an increase in collagen synt hesis, deposition, and denaturation, and a decrease in undenatured collagen s. In young TNF1.6 mice, these changes in the ECM were associated with mark ed diastolic dysfunction as demonstrated by significantly reduced transmitr al Doppler echocardiographic E/A wave ratio. Anti-TNF-alpha treatment with adenoviral vector expressing soluble TNF-alpha receptor type I attenuated b oth MMP-2 and MMP-9 activity, prevented further collagen synthesis, deposit ion and denaturation, and preserved myocardial diastolic function in young, but not old, TNF1.6 mice. The results suggest a critical role of TNF-alpha and MMPs in myocardial matrix remodeling and functional regulation and sup port the hypothesis that both TNF-alpha and MMPs may serve as potential the rapeutic targets in the treatment of heart failure.