Toldo Stefano, Mauro Adolfo G, Marchetti Carlo, Rose Scott W, Mezzaroma Eleonora, Van Tassell Benjamin W, Kim Soohyun, Dinarello Charles A, Abbate Antonio
*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.
J Cardiovasc Pharmacol. 2016 Jul;68(1):27-32. doi: 10.1097/FJC.0000000000000383.
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.
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.
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).
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.
α-1抗胰蛋白酶（AAT）是一种具有中性粒细胞弹性蛋白酶抑制活性的丰富血浆蛋白，且AAT可作为一种血浆来源的治疗药物（pAAT）。在实验性心肌梗死中，pAAT可减轻因缺血再灌注导致的急性炎症损伤。本研究的目的是评估在实验性心肌梗死中，一种由人AAT与人免疫球蛋白（Ig）G1 Fc片段融合而成的重组蛋白（rhAAT-Fc）的特性。
对10周龄的CD1雄性小鼠进行左冠状动脉前降支短暂闭塞（30分钟）。再灌注时给予rhAAT-Fc（2mg/kg）或pAAT（60mg/kg）。我们使用人血浆来源的Ig（2mg/kg）或等体积的0.9%氯化钠溶液作为对照溶液。24小时后，对梗死面积和半胱天冬酶-1活性进行定量分析。在24小时和7天时通过超声心动图测量左心室射血分数（LVEF）。还测试了一种缺乏弹性蛋白酶抑制活性的rhAAT-Fc变体，rhAAT-Fc。
rhAAT-Fc使梗死面积显著减小（与所有对照组相比，P<0.01；与pAAT相比，P>0.05）。rhAAT-Fc和pAAT使半胱天冬酶-1活性降低程度相同（降低70%；P<0.05；rhAAT-Fc与pAAT相比，P>0.05）。单次给药后对梗死面积的影响在24小时和7天时表现为LVEF得以保留（所有P<0.05）。缺乏弹性蛋白酶抑制活性的rhAAT-Fc，rhAAT-Fc，对梗死面积、半胱天冬酶-1活性和LVEF的影响相当（与rhAAT-Fc相比，P>0.2）。
pAAT和重组人AAT-Fc可减轻小鼠缺血再灌注后的急性心肌炎症损伤，从而保护存活心肌和收缩功能，这与对中性粒细胞弹性蛋白酶的作用无关。
