Therapeutic targeting of tissue inhibitor-4 in hypertrophy and failure

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Heart failure (HF) continues to be a leading cause of morbidity and mortality, and one form of HF that is increasing to near epidemic proportions is that which arises from a sustained pressure overload (LVPO). LVPO is invariably associated with increased extracellular matrix (ECM) remodeling, causing increased myocardial stiffness, impaired diastolic function, and the signs and symptoms of HF. One unifying observation is that with LVPO and the progression to HF, a shift in the relative balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) occur. More specifically, it is now recognized that a large diversity exists with respect to TIMP expression and function. TIMP-4 has been shown to alter fibroblast proliferation, survival, and collagen expression, and we have now identified that in contrast to that of TIMP-1, increased myocardial levels of TIMP-4 may actually prevent abnormal ECM remodeling and dysfunction with LVPO. This project will test the central hypothesis that HF progression with LVPO is due to inadequate TIMP-4 induction, thereby causing a shift in the TIMP stoichiometric balance favoring fibroblast transformation, ECM accumulation, increased myocardial stiffness, and thus drives the HF process forward. There are 3 aims of this project. Specific Aim 1 will establish that a transition to HF with LVPO can be predicted by a shift in TIMP-1/TIMP-4 balance and that this represents a tipping point whereby a shift in fibroblast transformation and proliferation occurs, accompanied by increased transforming growth factor (TGF) signaling and ECM accumulation, causing a rapid rise in regional myocardial stiffness. Specific Aim 2 will demonstrate that in a progressive model of LVPO in pigs, regional augmentation of recombinant TIMP-4 (rTIMP-4) through a novel hydrogel delivery system will prevent fibroblast transformation, ECM accumulation, and myocardial stiffness. Moreover, we will demonstrate that localized release of rTIMP-4 following the development of LVPO will reverse this ECM phenotype and thereby reduce myocardial stiffness. In Specific Aim 3, we will advance our delivery of rTIMP-4 to an intracoronary approach and demonstrate an interruption in the progression to HF with LVPO. Through an integrated set of translational studies, the outcomes from this project will define a new insight into how TIMPs, such as TIMP-4, contribute to the development of HF secondary to LVPO, provide a readily translatable approach in terms of a new diagnostic that can be used to predict the progression of this HF process, and finally establish a novel therapeutic direction for this significant cause of HF.