Self-Assembling Peptide Nanofibers for MMP Delivery and Cardiac Regeneration in Diabetes

Diabetes is a serious problem in the United States, afflicting 7.8% of the population with annual medical costs estimated at $116B in 2007 (1). Diabetic cardiomyopathy (DCM) is a cardiovascular complication of diabetes resulting in pathological alterations to the myocardium including circulatory defects, impaired heart muscle contraction, and progressive fibrosis. Cardiac fibrosis is associated with an imbalance between the deposition of the extracellular matrix (ECM) proteins by cardiac fibroblasts and the ECM proteolytic degradation via matrix metalloproteinases (MMPs). Recent studies have demonstrated that in the diabetic heart, expression and activity of MMP-2 are reduced, resulting in increased collagen accumulation and cardiac dysfunction (2). These observations suggest that a MMP-related mechanism may contribute to cardiac fibrosis, and that it may be attenuated through stimulation of native MMP-2 expression or delivery of exogenous MMP-2. Therefore, reduced MMP-2 activity in DCM may represent a novel target for therapeutic treatment (3). To achieve this, a special proteolytically-stable delivery scaffold would be needed, because native ECM is rapidly degraded by MMPs. The goal of this study is to determine if self-assembling peptide nanofibers can be used for long-term (several weeks) MMP delivery and enhancement of cardiac remodeling. This study tests the hypothesis that increased MMP-2 concentration (native or exogenous) in the nanofiber environment will promote matrix remodeling in diabetic cardiac fibroblasts in vitro.