Marchetti Carlo, Toldo Stefano, Chojnacki Jeremy, Mezzaroma Eleonora, Liu Kai, Salloum Fadi N, Nordio Andrea, Carbone Salvatore, Mauro Adolfo Gabriele, Das Anindita, Zalavadia Ankit A, Halquist Matthew S, Federici Massimo, Van Tassell Benjamin W, Zhang Shijun, Abbate Antonio
*VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA; †Victoria Johnson Research Laboratories, Richmond, VA; ‡Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Departments of §Medicinal Chemistry; ‖Pharmacotherapy and Outcome Studies, and ¶Pharmaceutics Virginia Commonwealth University, Richmond, VA.
J Cardiovasc Pharmacol. 2015 Jul;66(1):1-8. doi: 10.1097/FJC.0000000000000247.
Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage.
We used 2 experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of nonischemic injury due to doxorubicin 10 mg/kg to determine whether the NLRP3 inflammasome preserved cardiac function after injury.
Treatment with the NLRP3 inflammasome inhibitor in the reperfused AMI model caused a significant reduction in infarct size measured at pathology or as serum cardiac troponin I level (-56% and -82%, respectively, both P < 0.001) and preserved left ventricular fractional shortening (LVFS, 31 ± 2 vs. vehicle 26% ± 1%, P = 0.003). In the non-reperfused AMI model, treatment with the NLRP3 inhibitor significantly limited LV systolic dysfunction at 7 days (LVFS of 20 ± 2 vs. 14% ± 1%, P = 0.002), without a significant effect on infarct size. In the doxorubicin model, a significant increase in myocardial interstitial fibrosis and a decline in systolic function were seen in vehicle-treated mice, whereas treatment with the NLRP3 inhibitor significantly reduced fibrosis (-80%, P = 0.001) and preserved systolic function (LVFS 35 ± 2 vs. vehicle 27% ± 2%, P = 0.017).
Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction after ischemic and nonischemic injury in the mouse.
心肌损伤引发的无菌性炎症激活NLRP3炎性小体并放大炎症反应，介导进一步损伤。
我们使用了2种缺血性损伤实验模型（有再灌注和无再灌注的急性心肌梗死[AMI]）以及一种由10 mg/kg阿霉素导致的非缺血性损伤模型，以确定NLRP3炎性小体在损伤后是否能保留心脏功能。
在再灌注AMI模型中，用NLRP3炎性小体抑制剂治疗导致病理测量的梗死面积或血清心肌肌钙蛋白I水平显著降低（分别降低56%和82%，均P<0.001），并保留左心室缩短分数（LVFS，31±2对载体组26%±1%，P = 0.003）。在未再灌注AMI模型中，用NLRP3抑制剂治疗在7天时显著限制了左心室收缩功能障碍（LVFS为20±2对14%±1%，P = 0.002），对梗死面积无显著影响。在阿霉素模型中，载体治疗的小鼠出现心肌间质纤维化显著增加和收缩功能下降，而用NLRP3抑制剂治疗显著减少纤维化（-80%，P = 0.001）并保留收缩功能（LVFS 35±2对载体组27%±2%，P = 0.017）。
NLRP3炎性小体的药理学抑制可限制小鼠缺血性和非缺血性损伤后的细胞死亡和左心室收缩功能障碍。
