Laboratory of Experimental Intensive Care & Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Amsterdam, the Netherlands.
J Cardiovasc Pharmacol. 2019 Oct;74(4):271-275. doi: 10.1097/FJC.0000000000000696.
The NLRP3 inflammasome may contribute to infarct development during acute cardiac ischemia-reperfusion (IR). Because infarct size strongly correlates with the degree of heart failure in the long term, therapies that reduce reperfusion injury are still needed as first primary care against heart failure development. Inhibition of the NLRP3 inflammasome is currently viewed as such a potential therapy. However, previous research studies directed at inhibition of various inflammatory pathways in acute cardiac IR injury were often disappointing. This is because inflammation is a double-edged sword, detrimental when hyperactive, but beneficial at lower activity, with activity critically dependent on time of reperfusion and cellular location. Moreover, several inflammatory mediators can also mediate cardioprotective signaling. It is reasonable that this also applies to the NLRP3 inflammasome, although current literature has mainly focused on its detrimental effects in the context of acute cardiac IR. Therefore, in this review, we focus on beneficial, cardioprotective properties of the NLRP3 inflammasome and its components NLRP3, ASC, and caspase-1. The results show that (1) NLRP3 deficiency prevents cardioprotection in isolated heart by ischemic preconditioning and in vivo heart by TLR2 activation, associated with impaired STAT3 or Akt signaling, respectively; (2) ASC deficiency also prevents in vivo TLR2-mediated protection; and (3) caspase-1 inhibition results in decreased infarction but impaired protection through the Akt pathway during mild ischemic insults. In conclusion, the NLRP3 inflammasome is not only detrimental, it can also be involved in cardioprotective signaling, thus fueling the future challenge to acquire a full understanding of NLRP3 inflammasome role in cardiac IR before embarking on clinical trials using NLRP3 inhibitors.
NLRP3 炎性小体可能有助于急性心肌缺血再灌注 (IR) 期间的梗死发展。由于梗死面积与长期心力衰竭的程度密切相关，因此仍需要减少再灌注损伤的治疗方法作为预防心力衰竭发展的首要初级治疗。抑制 NLRP3 炎性小体目前被认为是一种潜在的治疗方法。然而，以前针对急性心脏 IR 损伤中各种炎症途径的抑制的研究通常令人失望。这是因为炎症是一把双刃剑，过度活跃时有害，但活性较低时有益，活性严重依赖于再灌注时间和细胞位置。此外，几种炎症介质也可以介导心脏保护信号。NLRP3 炎性小体也适用这一原理是合理的，尽管目前的文献主要集中在其在急性心脏 IR 背景下的有害作用。因此，在这篇综述中，我们重点关注 NLRP3 炎性小体及其组成部分 NLRP3、ASC 和 caspase-1 的有益的、心脏保护特性。结果表明：（1）NLRP3 缺乏通过缺血预处理阻止离体心脏的心脏保护作用，通过 TLR2 激活阻止体内心脏的心脏保护作用，分别与 STAT3 或 Akt 信号转导受损有关；（2）ASC 缺乏也会阻止体内 TLR2 介导的保护；（3）caspase-1 抑制会导致轻度缺血性损伤时 Akt 通路减少梗死，但保护作用受损。总之，NLRP3 炎性小体不仅有害，还可以参与心脏保护信号转导，因此在使用 NLRP3 抑制剂进行临床试验之前，进一步研究 NLRP3 炎性小体在心脏 IR 中的作用，以全面了解其作用是未来的挑战。
