Abstract 126: Gene Deletion of Dipeptidyl Peptidase I Reduces Myocyte Loss and Preserves Cardiac Function After Myocardial Ischemia-Reperfusion Injury

Introduction and Hypothesis: Chronic inflammation predisposes tissue to adverse cardiac remodeling and contributes to heart failure (HF) progression. The mechanisms whereby inflammation contributes to cardiac remodeling after cardiac injury has largely focused on action of reactive oxygen species and cytokines/chemokines and their role on myocyte growth and extracellular matrix (ECM) remodeling. However, the role of inflammatory proteases on myocyte loss and adverse cardiac remodeling has not been studied and are the focus of this study. Methods and Results: We subjected wild type and mice lacking Dipeptidyl peptidase I (DPPI), a lysosomal enzyme involved in the cleavage and activation of major inflammatory serine proteases, to myocardial ischemia for 30 min followed by reperfusion for 24hrs (IRI) and assessed the role of DPPI gene deletion on inflammatory proteases activation, myocyte apoptosis and cardiac remodeling and function. DPPI KO mice show markedly reduced inflammatory serine protease activity in response to myocardial IRI compared to wild type mice. DPPI deletion also markedly reduced myocyte apoptosis, limited infarct size and improved cardiac function in response to IRI. The role of inflammatory serine proteases in cardiac remodeling was further demonstrated after in-vivo cardiac transfer of cathepsin G, a neutrophil derived serine protease that has been shown to induce myocyte death in-vitro. Mice with cathepsin G injection for 5 days show increased interstitial collagen degradation and myocyte apoptosis and presented cardiac dilatation and contractile dysfunction. Conclusions: These findings reveal the role of DPPI as a key mediator of postischemic/reperfusion injury and show that inflammatory derived proteases contribute to the pathological cardiac remodeling and dysfunction.