batimastat and Heart-Failure

Matrix metalloproteinases (MMPs) are a family of functionally related zinc-containing enzymes that denature and degrade fibrillar collagens and other components of the extracellular matrix. Myocardial extracellular matrix remodelling and fibrosis regulated by MMPs are believed to be important contributors to the progression of heart failure. The role of MMPs in cardiac fibrosis and the progression of heart failure, along with the possibility of halting the progression of heart failure by modulating extracellular matrix remodelling are important issues under intense study. MMPs are increased in the failing hearts of both animal models and patients with heart failure. MMP inhibition may therefore modulate extracellular matrix remodelling and the progression of heart failure. It is a great advantage that various MMP inhibitors have been developed initially for the treatment of cancer, arthritis and other diseases believed to be associated with increased MMP activity. Several preclinical studies have shown that treatment of heart failure in animal models with MMP inhibitors results in less collagen matrix damage, favourable extracellular matrix remodelling, and improved cardiac structure and function. The results suggest that modulation of MMP activity can prevent myocardial dysfunction and the progression of heart failure through alterations in the remodelling process of extracellular matrix and the left ventricle. Although these promising results suggest potential benefits of MMP inhibition for human heart failure, no clinical data evaluating MMP inhibitors in heart failure have been reported. As the preclinical evidence continues to grow and the potential of MMP inhibition for the treatment of heart failure continues to unfold, MMP inhibition may prove to be an effective treatment for heart failure.

Topics: Animals; Enzyme Inhibitors; Extracellular Matrix; Heart Failure; Humans; Inhibitory Concentration 50; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Myocardium; Phenylalanine; Thiophenes

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.

Topics: Animals; Collagen; Enzyme Inhibitors; Heart Failure; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Transgenic; Myocardium; Phenotype; Phenylalanine; Reference Values; Survival; Thiophenes; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Increased plasma levels of endothelin-1 (ET-1) occur with congestive heart failure (CHF), but the components of the enzymatic activation of ET-1 in the myocardium remain to be defined. Accordingly, endothelin converting enzyme-1 (ECE-1) activity and expression in normal and failing heart were examined.. Left ventricular (LV) tissue samples were obtained from patients undergoing heart transplantation because of dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) and from normal donor hearts. The gene expression of ET-1 precursor and ECE-1a was upregulated 4- and 3-fold, respectively, in the failing heart. ECE-1 activity (fmol/mg protein per hour) was augmented from 2,291+/-257 in normal tissue samples to 5,507+/-666 in DCM samples and to 7,435+/-682 in ICM samples (P < .05). Phosphoramidon and a specific ECE-1 inhibitor, FR901533, inhibited ECE-1 activity by over 90%. However, inhibitors of neutral endopeptidase (thiorphan) and matrix metalloproteases (batimistat) did not affect the conversion of big ET-1 to ET-1.. This study showed that the biosynthetic pathway of ET-1 is activated in LV myocardium in the failing heart, and the myocardial processing of big ET-1 is highly specific for ECE-1.

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Cardiomyopathy, Dilated; Case-Control Studies; Endothelin-Converting Enzymes; Gene Expression Regulation; Heart Failure; Heart Transplantation; Heart Ventricles; Humans; Metalloendopeptidases; Phenylalanine; Reverse Transcriptase Polymerase Chain Reaction; Tetracyclines; Thiophenes; Up-Regulation