Targeting inflammatory serine proteases for cardiac repair after Ischemia Reperfusion injury (1080.10)

Abstract

Background: Chronic inflammation predisposes tissue to adverse cardiac remodeling and contributes to heart failure (HF) progression. The mechanisms whereby inflammation affect cardiac remodeling after injury has largely focused on action of reactive oxygen species and cytokines/chemokines. However, inflammatory cells also release serine proteases and their role in myocyte loss and adverse cardiac remodeling remains largely unknown.Methods and Results: We subjected mice to myocardial ischemia for 30 minutes followed by reperfusion for 24 hours (IRI) and assessed the effect of inflammatory serine protease (ISP) inhibitor, a potent non peptide inhibitor of cathepsin G, chymase and tryptase, on myocyte apoptosis, infarct size and cardiac function. ISP inhibitor was delivered just after reperfusion either systemically (10 mg/kg, i.v.) or encapsulated in anti‐P‐selectin conjugated immunoliposomes (2 mg/kg, i.v.). Treatment with ISP inhibitor loaded immunoliposomes reduced cathepsin G and chymase activity induced after IRI compared to mice treated with empty immunoliposomes. Targeted delivery of ISP inhibitor also reduced myocyte apoptosis, limited infarct size and improved cardiac function in response to IRI. These structural and functional improvements of targeted delivery of ISP inhibitor were similar to those obtained with systemic delivery of ISP inhibitor at higher dose, but have the advantage to occur without detectable side effects of ISP inhibition on spleen, bone marrow and circulating leukocytes.Conclusions: These findings reveal the role of ISPs as key mediators of myocyte apoptosis and cardiac dysfunction post‐IRI and show that targeted inhibition of ISPs could be used as a therapy to reduce pathological cardiac remodeling and dysfunction associated with myocardial infarction.Grant Funding Source: NIH R01360998