MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure.
Myocardial extracellular matrix remodeling regulated by matrix metalloproteinases (MMPs) is implicated in the progression of heart failure. We hypothesized that MMP inhibition may modulate extracellular matrix remodeling and prevent the progression of heart failure. The effects of the MMP inhibitor BB-94 (also known as batimastat) on MMP expression, collagen expression, collagen deposition, collagen denaturation, and left ventricular structure and function in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor-alpha (TNF-alpha) (TNF1.6) were assessed. The results showed that BB-94 reduced the expression of collagens, increased insoluble collagen and the ratio of undenatured to total soluble collagen, and prevented myocardial hypertrophy and diastolic dysfunction in young TNF1.6 mice. Furthermore, the treatment significantly improved cumulative survival of TNF1.6 mice. However, MMP inhibition did not have salutary effects on ventricular size and function in old mice with established heart failure. The results suggest that MMP activation may play a critical role in changes of myocardial function through the remodeling of extracellular matrix, and MMP inhibition may serve as a potential therapeutic strategy for heart failure, albeit within a narrow window during the development of heart failure.
Li
Yun You
YY
Cardiovascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. liyuny@pitt.edu
Kadokami
Toshiaki
T
Wang
Ping
P
McTiernan
Charles F
CF
Feldman
Arthur M
AM
D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology; D010641:Phenotype; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012016:Reference Values; D013534:Survival; D013876:Thiophenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D016277:Ventricular Function, Left / Q000502:physiology
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D010649:Phenylalanine; D003094:Collagen; C080985:batimastat; D020782:Matrix Metalloproteinases