抑制NLRP3炎性小体可限制小鼠心肌缺血再灌注后的炎症损伤。

Inhibition of the NLRP3 inflammasome limits the inflammatory injury following myocardial ischemia-reperfusion in the mouse.

作者信息

Toldo Stefano, Marchetti Carlo, Mauro Adolfo G, Chojnacki Jeremy, Mezzaroma Eleonora, Carbone Salvatore, Zhang Shijun, Van Tassell Benjamin, Salloum Fadi N, Abbate Antonio

机构信息

VCU Pauley Heart Center, Virginia Commonwealth University, United States; Department of Surgery, Division of Cardio-thoracic Surgery, Virginia Commonwealth University, United States; Johnson Research Center for Critical Care, Virginia Commonwealth University, United States.

VCU Pauley Heart Center, Virginia Commonwealth University, United States; Johnson Research Center for Critical Care, Virginia Commonwealth University, United States.

出版信息

Int J Cardiol. 2016 Apr 15;209:215-20. doi: 10.1016/j.ijcard.2016.02.043. Epub 2016 Feb 4.

DOI:10.1016/j.ijcard.2016.02.043

PMID:26896627

Abstract

BACKGROUND

Successful reperfusion is the most effective strategy to reduce ischemic injury in acute myocardial infarction (AMI). Ischemic injury, however, also triggers a secondary ischemia-independent injury, known as reperfusion injury, contributing to the overall infarct size. We hypothesize that inhibition of the Nod-like Receptor Protein-3 (NLRP3) inflammasome limits infarct size following myocardial ischemia/reperfusion (I/R), by inhibiting the inflammatory component of the reperfusion injury.

METHODS

CD-1 male mice underwent transient ligation of the left anterior descending coronary artery for 30 or 75min followed by reperfusion. Infarct size was measured at 1, 3 and 24h. A NLRP3 inflammasome inhibitor (NLRP3inh) or vehicle was administrated immediately at time of reperfusion or with a delay of 1 or 3h of reperfusion.

RESULTS

A time-dependent increase in infarct size was measured at 1, 3, and 24h after reperfusion (11±2%, 30±5% and 43±4% of the area at risk respectively; P<0.001 for trend). NLRP3 myocardial expression was significantly increased at 24h and 6h vs 3h (P<0.01). Administration of the NLRP3inh at reperfusion did not reduce infarct size at 3h, while it significantly reduced infarct size at 24h (-56% vs vehicle, P<0.01). The NLRP3inh given 1h after reperfusion also significantly decreased caspase-1 activity and infarct size measured at 24h, whereas the NLRP3inh did not when given with a delay of 3h.

CONCLUSIONS

Pharmacological inhibition of the NLRP3 inflammasome within 1h of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia-reperfusion in the mouse.

摘要

背景

成功的再灌注是减少急性心肌梗死（AMI）缺血性损伤的最有效策略。然而，缺血性损伤也会引发一种继发性的非缺血依赖性损伤，即再灌注损伤，这会导致整体梗死面积增大。我们假设抑制Nod样受体蛋白3（NLRP3）炎性小体可通过抑制再灌注损伤的炎症成分来限制心肌缺血/再灌注（I/R）后的梗死面积。

方法

CD-1雄性小鼠接受左前降支冠状动脉短暂结扎30或75分钟，随后进行再灌注。在再灌注后1、3和24小时测量梗死面积。在再灌注时或再灌注延迟1或3小时后立即给予NLRP3炎性小体抑制剂（NLRP3inh）或赋形剂。

结果

再灌注后1、3和24小时测量到梗死面积呈时间依赖性增加（分别为危险区域面积的11±2%、30±5%和43±4%；趋势P<0.001）。与3小时相比，NLRP3在心肌中的表达在24小时和6小时显著增加（P<0.01）。再灌注时给予NLRP3inh在3小时时并未减少梗死面积，而在24小时时显著减少了梗死面积（与赋形剂相比为-56%，P<0.01）。再灌注1小时后给予NLRP3inh也显著降低了24小时时测量的半胱天冬酶-1活性和梗死面积，而延迟3小时给予NLRP3inh则没有这种效果。