application) Congestive heart failure (CHF) is a significant cause of morbidity and mortality worldwide. The incidence of CHF is increasing and the one year survival rate after development of severe symptoms is less than 40%. While CHF can arise from a number of factors, a common event in the transition to severe CHF is left ventricular (LV) remodeling and progressive dilation. Fundamental mechanisms which contribute to the initial changes in LV geometry with the progression of CHF remain unknown. The collagenases, or matrix metalloproteinases (MMPs), have been demonstrated to play a significant role in tissue remodeling such as in tumor metastases and inflammation, but the functional role of MMPs within the LV myocardium remain unclear. The central hypothesis of this project is that increased collagenase, or MMP activity, is an initial contributory event for the progressive LV dilation with CHF. Interruption of specific LV MMP activity through direct inhibition will significantly ameliorate or delay the LV dilation and dysfunction which inevitably occurs with CHF. This project will use an animal model of pacing induced CHF, which has many of the same phenotypic characteristics of clinical CHF, in order to test this central hypothesis. The project will be executed in a step-wise fashion in order to accomplish the following specific aims: (1) Quantitative time dependent changes in MMP expression, content, and activity as well as collagen structure and content with pacing CHF. (2) Identify specific forms of MMPs which are selectively increased during the development of CHF and elucidate candidate molecular mechanisms responsible for the early up-regulation of these MMP species within the LV myocardium. (3) Following identification of the temporal sequence and specific mechanisms responsible for collagen degradation and MMP activation with CHF, specifically inhibit these processes and quantitative the effects on LV function and geometry. This project will identify potential mechanisms responsible for the initiation of the LV remodeling which occurs with CHF as well as develop strategies to inhibit these early structural events. Accordingly, this project is clinically significant in that it will identify a new therapeutic approach in preventing the progressive LV dilation and dysfunction which accompanies the transition to severe CHF.
Showing the most recent 10 out of 87 publications
