Abstract 14752: Recombinant Alpha-1-Antitrypsin Reduces Myocardial Ischemia-Reperfusion Injury in the Mouse
Objectives: Alpha-1-antitrypsin (AAT) is a plasma protein, which inhibits neutrophil elastase and is available as a plasma-derivative therapeutic for AAT deficient patients. In experimental myocardial infarction (MI), plasma-derived AAT (pAAT) reduced ischemia-reperfusion (I-R) injury. Because the use of pAAT is hindered by limited supply, risk of viral transmission and degradation during the extensive isolation process, we evaluated a recombinant fusion protein composed of human AAT and human immunoglobulin (Ig) G1 Fc fragment (rAAT-Fc) in experimental MI.
Methods: Ten week old CD1 male mice underwent transient occlusion (30 min) of the left anterior coronary artery. rAAT-Fc (2 mg/kg) or pAAT (60 mg/kg) were administered (0.2 ml) upon reperfusion. NaCl 0.9% (0.2 ml), human i.v. IgG (2 mg/kg) or human albumin (60 mg/kg) were used as controls. After 24 hours, infarct size (tetrazolium chloride) and the caspase-1 activity was quantified in heart homogenates as a measure of the inflammatory injury to the heart. The left ventricular fractional shortening (LVFS) was measured by echocardiography at 24 hours and 7 days. A variant of rAAT-Fc lacking elastase inhibition activity was also tested.
Results: rAAT-Fc induced a dose-dependent reduction in infarct size and in caspase-1 activity in the heart tissue (p<0.05 vs control; p>0.05 vs pAAT, Figure). The effects on infarct size were reflected in a preservation of LV systolic function (LVFS) at 24 hours (Figure) and 7 days after a single administration. A modified rAAT-Fc without elastase inhibiting activity conferred comparable effects on infarct size, caspase-1 activity and LVFS (p<0.05 vs control, P>0.05 vs pAAT).
Conclusions: Recombinant AAT-Fc reduces inflammatory myocardial injury following ischemia-reperfusion in the mouse leading to preservation of viable myocardium and systolic function, independent of inhibition of neutrophil elastase.
- © 2013 by American Heart Association, Inc.