<br>SIRT1 激动在缺血和再灌注过程中通过丙酮酸脱氢酶调节心脏 NLRP3 炎症小体,Redox Biology

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SIRT1 激动在缺血和再灌注过程中通过丙酮酸脱氢酶调节心脏 NLRP3 炎症小体
Redox Biology ( IF 10.7 ) Pub Date : 2020-04-13 , DOI: 10.1016/j.redox.2020.101538
Ying Han ₁ , Weiju Sun ₂ , Di Ren ₃ , Jingwen Zhang ₃ , Zhibin He ₃ , Julia Fedorova ₃ , Xiaodong Sun ₄ , Fang Han ₄ , Ji Li ₃

Affiliation

具有 Pyrin 结构域 3 (NLRP3) 炎性体的核苷酸结合寡聚化结构域样受体已成为代谢失调的标志物。我们发现，年龄相关的 Sirtuin-1 (SIRT1) 调节心脏代谢，从而调节缺血和再灌注 (I/R) 应激期间的炎症反应。我们假设 SIRT1 通过代谢调节减轻心肌缺血再灌注期间 NLRP3 炎症小体依赖性炎症和细胞焦亡。对 C57BL/6J 野生型 (WT) 小鼠、诱导型心肌细胞特异性 SIRT1 敲除 (icSIRT1 KO) 和诱导型心肌细胞特异性 PDH E1α 敲除 (icPDH E1α KO) 小鼠进行左冠状动脉前降支结扎和释放，用于区域 I/R 模型。超声心动图测量表明，SIRT1 激动剂 SRT1720 (30 μg/g) 可改善 C57BL/6J WT 小鼠缺血 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 SIRT1 激动剂 SRT1720 抑制 I/R 诱导的 PDH 活性，并减少心肌 I/R 期间活性氧 (ROS) 的产生。此外，SRT1720 在 I/R 过程中调节 PDH 相关的葡萄糖氧化代谢，以 Akt 信号依赖方式减少 NLRP3 炎性体激活和细胞焦亡。此外，在 I/R 应激下，icSIRT1 KO 小鼠与 SIRT1 小鼠中观察到 Akt 信号传导受损。有趣的是，我们观察到 I/R 期间 icPDH E1α KO 心脏与 PDH E1α 心脏相比，ROS 生成水平较低，NLRP3 水平降低，焦亡发生较少。综上所述，结果表明，在 I/R 引起的缺血性损伤期间，SIRT1 激动剂可以通过 Akt 依赖性代谢调节抑制 NLRP3 炎症小体的激活。

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SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion

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 E1α knockout (icPDH E1α KO) mice were subjected to ligation and release of left anterior descending coronary artery for regional I/R models. The echocardiography measurement demonstrated that SIRT1 agonist SRT1720 (30 μg/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 mice under I/R stress. Intriguingly, we observed lower levels of ROS generation, decreased NLRP3 levels and less pyroptosis occurred in the icPDH E1α KO versus PDH E1α 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.

更新日期：2020-04-13

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