| The matrix metalloproteinases (MMPs) are members of a family of metal-dependent enzymes that preferentially degrade extracellular matrix components. The MMPs are secreted in a zymogen form which becomes activated by other proteolytic enzymes as well as by other MMP species in the extracellular space. The tissue inhibitors of matrix metalloproteinases (TIMPs) are endogenous, inhibitors of the MMPs which can thwart this enzymatic activation in the extracellular space. It is likely that this method of activation, and the presence of the TIMPs, allows for a tight control on MMP enzymatic activity. Past studies have implicated that the MMPs play a major role in tissue remodeling states such as carcinoma. With the development and progression of heart failure, extensive remodeling of the left ventricular (LV) myocardial extracellular matrix occurs. The objectives of this project were to determine (1) which MMP species are present in the myocardium, (2) whether changes in MMP expression exist in disease states accompanied by LV remodeling, and (3) whether LV myocardial myocytes synthesize MMPs which can be affected by extracellular stimuli relevant to cardiac disease. These studies have demonstrated the existence of several MMP species in the myocardium, and showed that changes in MMP expression and activity are associated wit h the LV remodeling that occurs during the development and progression of heart failure. In vitro studies performed with isolated LV myocyte preparations have shown that LV myocytes synthesize specific MMP species, such as MMP-2, which specifically degrade basement membrane components. Additional experiments demonstrated that the activation of specific neurohormonal systems which are important in heart failure, such as the β-adrenergic, endothelin-1, and angiotensin-II receptor pathways, influences LV myocyte MMP synthesis and release. The results of these experiments suggest that the LV remodeling which occurs during the development and progression of heart failure may be a consequence of altered LV myocyte MMP production in response to extracellular neurohormonal stimulation. |
