VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
J Mol Cell Cardiol. 2011 Aug;51(2):244-51. doi: 10.1016/j.yjmcc.2011.05.003. Epub 2011 May 12.
Alpha-1-antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties. Here, we studied the effects of exogenously administered AAT on caspase-1 activity and on the outcome of ischemia-reperfusion injury (I/R) in a mouse model of acute myocardial infarction (AMI). Adult male mice underwent 30 min of coronary artery ligation followed by reperfusion and were randomly assigned to receive clinical-grade AAT or albumin at reperfusion. Infarct size was evaluated after 1 and 7 days. Caspase-1 activity was measured in homogenates of heart tissue. Left ventricular (LV) end-diastolic diameter (EDD) and end-systolic diameter (ESD) were measured and LV fractional shortening (FS) and ejection fraction (EF) were calculated using transthoracic echocardiography. The effect of AAT on caspase-1 activity was determined in cultures of mouse HL-1 cardiomyocytes stimulated with LPS and triggered with nigericin or when HL-1 cells were exposed to simulated ischemia. AAT-treated mice had significantly smaller infarct sizes (-30% day 1 and -55% day 7) compared with mice treated with albumin. AAT treatment resulted in >90% reduction in caspase-1 activity in homogenates of hearts 24h after I/R. Seven days after AMI, AAT-treated mice exhibited a >90% smaller increase in LVEDD and LVESD and smaller reduction in LVEF. The increase in caspase-1 activity in HL-1 cells induced by LPS and nigericin or following exposure to simulated ischemia was reduced by >80% and AAT similarly reduced cell death by >50%. In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling.
α-1 抗胰蛋白酶（AAT）具有抗炎和组织保护特性。在这里，我们研究了外源性给予 AAT 对 caspase-1 活性以及在急性心肌梗死（AMI）小鼠模型中缺血再灌注损伤（I/R）结果的影响。成年雄性小鼠接受 30 分钟的冠状动脉结扎，然后再灌注，并在再灌注时随机接受临床级 AAT 或白蛋白治疗。在 1 天和 7 天后评估梗死面积。在心脏组织匀浆中测量 caspase-1 活性。使用经胸超声心动图测量左心室（LV）舒张末期直径（EDD）和收缩末期直径（ESD），并计算 LV 缩短分数（FS）和射血分数（EF）。通过用 LPS 刺激的小鼠 HL-1 心肌细胞的培养物以及用 Nigericin 触发或当 HL-1 细胞暴露于模拟缺血时来确定 AAT 对 caspase-1 活性的影响。与用白蛋白治疗的小鼠相比，用 AAT 治疗的小鼠的梗死面积明显较小（第 1 天为-30%，第 7 天为-55%）。I/R 后 24 小时，AAT 治疗的心脏匀浆中的 caspase-1 活性降低了>90%。在 AMI 后 7 天，用 AAT 治疗的小鼠的 LVEDD 和 LVESD 增加幅度减小了>90%，LVEF 降低幅度减小了>90%。LPS 和 Nigericin 诱导或模拟缺血后 HL-1 细胞中 caspase-1 活性的增加减少了>80%，AAT 同样减少了>50%的细胞死亡。总之，外源性给予临床级 AAT 可降低缺血心肌中的 caspase-1 活性，从而保存存活心肌并预防不良的心脏重构。
