Recombinant Human Alpha-1 Antitrypsin-Fc Fusion Protein Reduces Mouse Myocardial Inflammatory Injury After Ischemia–Reperfusion Independent of Elastase Inhibition

    loading  Checking for direct PDF access through Ovid

Abstract

Background:

Alpha-1-antitrypsin (AAT) is an abundant plasma protein with neutrophil elastase-inhibiting activity, and AAT is available as a plasma-derived therapeutic (pAAT). In experimental myocardial infarction, pAAT reduced acute inflammatory injury because of ischemia–reperfusion. The aim of the present study was to assess the properties of a recombinant protein composed of human AAT fused to the human immunoglobulin (Ig) G1 Fc fragment (rhAAT-Fc) in experimental myocardial infarction.

Methods:

Ten-week-old CD1 male mice underwent transient occlusion (30 minutes) of the left anterior coronary artery. rhAAT-Fc (2 mg/kg) or pAAT (60 mg/kg) were administered upon reperfusion. We used human plasma-derived Ig (2 mg/kg) or a matching volume of NaCl 0.9% as control solutions. After 24 hours, infarct size and caspase-1 activity were quantified. The left ventricular ejection fraction (LVEF) was measured by echocardiography at 24 hours and 7 days. A variant of rhAAT-Fc lacking elastase inhibition activity, rhAAT-Fc[E−], was also tested.

Results:

The rhAAT-Fc induced a significant reduction in infarct size (P < 0.01 vs. all controls, P > 0.05 vs. pAAT). Caspase-1 activity was reduced to the same degree with rhAAT-Fc and pAAT (−70%; P < 0.05; P > 0.05 rhAAT-Fc vs. pAAT). The effects on infarct size after a single administration were reflected by preservation of LVEF at 24 hours and 7 days (all P < 0.05). rhAAT-Fc without elastase inhibiting activity, rhAAT-Fc[E−], conferred comparable effects on infarct size, caspase-1 activity, and LVEF (P > 0.2 vs. rhAAT-Fc).

Conclusions:

The pAAT and recombinant human AAT-Fc reduce the acute myocardial inflammatory injury after ischemia–reperfusion in the mouse leading to preservation of viable myocardium and systolic function, independent on the effects on neutrophil elastase.

Related Topics

    loading  Loading Related Articles