title: Recombinant Human Alpha-1 Antitrypsin-Fc Fusion Protein Reduces Mouse Myocardial Inflammatory Injury After Ischemia-Reperfusion Independent of Elastase Inhibition.
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, 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, 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.
authors.affiliation: *VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA; †VCU Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA; ‡Department of Surgery, Virginia Commonwealth University, Richmond, VA; §Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA; ‖Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea; ¶Department of Medicine, University of Colorado, Denver, CO; and #Department of Experimental Medicine, Radbound University Medical Center, Nijmegen, the Netherlands.
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Mauro
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.forename: Scott W
authors.initials: SW
authors.lastname: Rose
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014022:Tissue Survival; D016277:Ventricular Function, Left / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D002317:Cardiovascular Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; D020170:Caspase 1