Faculty Collaboration Database

Inhibition of matrix metalloproteinase activity prevents increases in myocardial tumor necrosis factor-alpha. J Mol Cell Cardiol 2010 Aug;49(2):245-50

Date

04/21/2010

Pubmed ID

20403361

Pubmed Central ID

PMC2885505

DOI

10.1016/j.yjmcc.2010.04.005

Scopus ID

2-s2.0-77953688654 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

TNF-alpha is known to cause adverse myocardial remodeling. While we have previously shown a role for cardiac mast cells in mediating increases in myocardial TNF-alpha, however, matrix metalloproteinase (MMP) activation of TNF-alpha may also be contributory. We sought to determine the relative roles of MMPs and cardiac mast cells in the activation of TNF-alpha in the hearts of rats subjected to chronic volume overload. Interventions with the broad spectrum MMP inhibitor, GM6001, or the mast cell stabilizer, nedocromil, were performed in the rat aortocaval fistula (ACF) model of volume overload. Myocardial TNF-alpha levels were significantly increased in the ACF. This increase was prevented by MMP inhibition with GM6001 (p< or =0.001 vs. ACF). Conversely, myocardial TNF-alpha levels were increased in the ACF+nedocromil treated fistula groups (p< or =0.001 vs. sham). The degradation of interstitial collagen volume fraction seen in the untreated ACF group was prevented in both the GM6001 and nedocromil treated hearts. Significant increases in LV myocardial ET-1 levels also occurred in the ACF group at 3days post-fistula. Whereas administration of GM6001 significantly attenuated this increase, mast cell stabilization with nedocromil markedly exacerbated the increase, producing ET-1 levels 6.5 fold and 2 fold greater than that in the sham-operated control and ACF group, respectively. The efficacy of the MMP inhibitor, GM6001, to prevent increased levels of myocardial TNF-alpha is indicative of MMP-mediated cleavage of latent extracellular membrane-bound TNF-alpha protein as the primary source of bioactive TNF-alpha in the myocardium of the volume overload heart.

Author List

Murray DB, Levick SP, Brower GL, Janicki JS

MESH terms used to index this publication - Major topics in bold

Animals
Cell Count
Cell Degranulation
Cytokines
Extracellular Matrix
Male
Mast Cells
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Myocardium
Neurotransmitter Agents
Rats
Rats, Sprague-Dawley
Tumor Necrosis Factor-alpha