SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion
SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion
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DOI：
10.1016/j.redox.2020.101538
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发表时间：
2020-07-01
期刊：
影响因子：
11.4
通讯作者：
Li, Ji
中科院分区：
文献类型：
--
作者：
Han, Ying;Sun, Weiju;Li, Ji
具有Pyrin结构域3的核苷酸结合寡聚化结构域样受体（NLRP 3）炎性体是代谢失调的标志物。我们发现，年龄相关的Sirtuin-1（SIRT 1）调节心脏代谢，介导缺血再灌注（I/R）应激过程中的炎症反应。我们假设SIRT 1通过代谢调节减弱心肌I/R过程中NLRP 3炎性小体依赖性炎症和焦亡。对C57 BL/6 J野生型（WT）小鼠、诱导型心肌细胞特异性SIRT 1敲除（icSIRT 1 KO）小鼠和诱导型心肌细胞特异性PDH E1 a敲除（icPDH E1 a KO）小鼠进行左前降支冠状动脉结扎和释放，用于体内局部I/R模型。超声心动图测量表明，SIRT 1激动剂SRT 1720（30 μ g/g）改善C57 BL/6 J WT小鼠在缺血45分钟和再灌注6小时期间的心脏收缩功能。生化分析表明，I/R触发心脏丙酮酸脱氢酶（PDH）的激活，而SIRT 1激动剂SRT 1720抑制I/R诱导的PDH活性，并减少心肌I/R过程中活性氧（ROS）的产生。此外，SRT 1720在I/R期间以Akt信号传导依赖性方式调节PDH相关的葡萄糖氧化代谢以减少NLRP 3炎性小体活化和焦亡。此外，在I/R应激下，在icSIRT 1 KO与SIRT 1（fox/flox）小鼠中观察到Akt信号传导受损。有趣的是，我们观察到在I/R期间，与PDH E1 α（flox/flox）心脏相比，icPDH E1 a KO心脏的ROS产生水平较低，NLRP 3水平降低，并且发生的焦亡较少。综上所述，结果表明，SIRT 1激动可以抑制I/R缺血损伤期间NLRP 3炎性体通过Akt依赖性代谢调节的活化。
Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) inflammasome was emerged as a marker of metabolic dysregulation. We revealed that age-related Sirtuin-1 (SIRT1) modulates cardiac metabolism that medicated inflammatory response during ischemia and reperfusion (I/R) stress. We hypothesize that SIRT1 attenuates NLRP3 inflammasome-dependent inflammation and pyroptosis during myocardial I/R through metabolic modulation. C57BL/6J wild type (WT) mice, inducible cardiomyocyte specific SIRT1 knockout (icSIRT1 KO) and inducible cardiomyocyte specific PDH E1a knockout (icPDH E1a KO) mice were subjected to ligation and release of left anterior descending coronary artery for in vivo regional I/R models. The echocardiography measurement demonstrated that SIRT1 agonist SRT1720 (30 mu g/g) improved cardiac systolic function during 45 min of ischemia and 6 h of reperfusion in C57BL/6J WT mice. The biochemical analysis showed that I/R triggered activation of cardiac pyruvate dehydrogenase (PDH), while SIRT1 agonist SRT1720 inhibited I/R-induced PDH activity and reduced production of reactive oxygen species (ROS) during myocardial I/R. Moreover, SRT1720 regulates PDH-related glucose oxidative metabolism to reduce NLRP3 inflammasome activation and pyroptosis in an Akt signaling dependent manner during I/R. Furthermore, an impaired Akt signaling was observed in icSIRT1 KO versus SIRT1(fox/flox) mice under I/R stress. Intriguingly, we observed lower levels of ROS generation, decreased NLRP3 levels and less pyroptosis occurred in the icPDH E1a KO versus PDH E1 alpha(flox/flox) hearts during I/R. Taken together, the results indicate that SIRT1 agonism can inhibit activation of NLRP3 inflammasome via Akt-dependent metabolic regulation during ischemic insults by I/R.