Neutrophils are thought to orchestrate myocardial remodeling during the early progression to cardiac failure through the release of reactive oxygen species, antimicrobial peptides, and proteases. Although neutrophil activation may be beneficial at early stages of disease, excessive neutrophil infiltration detrimentally leads to cardiomyocyte death and tissue damage. The neutrophil-derived serine protease cathepsin G (CG) has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis1. However the role of inflammatory serine proteases in cardiac remodeling and cardiac regeneration in-vivo is still unknown. We showed that cardiac injection of neutrophil derived protease led to early cardiac dilatation and dysfunction characterized by an increase in matrix metalloprotease (MMP) activation and extracellular matrix degradation along with an increase in myocyte death by apoptosis. To assess the role of these serine proteases, we used mice lacking dipeptidyl peptidase I (DPPI), an enzyme involved in major inflammatory protease activation. DPPI deficient mice demonstrated a more robust functional recovery after ischemia reperfusion (IR) and myocardial infarction (MI) injury, as well as significantly reduced myocyte apoptosis, cardiac dilatation, infarct size and mortality rate. Meanwhile, our data showed increased groups of cardiac stem cells and proliferating cardiac cells in the MI 7-days DPPI knockout mice. We also found enhanced DPPI expression in response to pathological stress stimuli in mice. These findings reveal an unrecognized role of DPPI as a key mediator of post-ischemia cardiac injury and show that inflammatory derived proteases may contribute to the pathological cardiac remodeling and cardiac regeneration, and may be considered as novel target for future therapies. / Physiology