CircHelz activates NLRP3 inflammasome to promote myocardial injury by sponging miR-133a-3p in mouse ischemic heart
CircHelz activates NLRP3 inflammasome to promote myocardial injury by sponging miR-133a-3p in mouse ischemic heart
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CircHelz 通过海绵 miR-133a-3p 激活小鼠缺血心脏中的 NLRP3 炎性体以促进心肌损伤
DOI：
10.1016/j.yjmcc.2021.05.010
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发表时间：
2021-06-07
影响因子：
5
通讯作者：
Yang, Baofeng
中科院分区：
文献类型：
--
作者：
Bian, Yu;Pang, Ping;Yang, Baofeng
众所周知，心肌梗死（MI）诱导的NLRP3炎性体的激活可通过引起心脏炎症和焦亡而加重心肌损伤和心功能障碍。环状rna （circRNAs）已被证明在心血管疾病中发挥关键作用。然而，环状rna在调节心脏炎症反应和心肌细胞焦亡中的功能和机制在很大程度上仍然未知。我们发现circHelz是一种由锌指解旋酶（Helz）基因转录而成的新型环状rna，在缺氧条件下心肌梗死小鼠和新生小鼠心室心肌细胞（NMVCs）缺血心肌中均显著上调。circHelz的过表达通过激活NLRP3炎性体和诱导焦亡，在NMVCs中引起心肌细胞损伤，而circHelz的沉默可降低缺氧诱导的这些作用。此外，circHelz的敲低显著降低了心肌梗死后NLRP3的表达，降低了心肌梗死面积、焦亡、炎症和心功能。心肌细胞中miR-133a-3p的过表达通过靶向NMVCs中的NLRP3，极大地阻止了缺氧或circHelz存在下的焦亡。从机制上讲，circHelz通过抑制miR-133a-3p的活性，起到内源性海绵的作用。总体而言，我们的研究结果表明，circHelz通过抑制miR-133a-3p功能，触发NLRP3炎症小体介导的促炎反应和随后的心肌细胞焦亡，从而导致心肌损伤。因此，干扰circHelz/miR133a-3p/NLRP3轴可能是一种很有前景的缺血性心脏病治疗方法。
Myocardial infarction (MI)-induced the activation of NLRP3 inflammasome has been well known to aggravate myocardial injury and cardiac dysfunction by causing inflammation and pyroptosis in the heart. Circular RNAs (circRNAs) have been demonstrated to play critical roles in cardiovascular diseases. However, the functions and mechanisms of circRNAs in modulating cardiac inflammatory response and cardiomyocyte pyroptosis remain largely unknown. We revealed that circHelz, a novel circRNA transcribed from the helicase with zinc finger (Helz) gene, was significantly upregulated in both the ischemic myocardium of MI mouse and neonatal mouse ventricular cardiomyocytes (NMVCs) exposed to hypoxia. Overexpression of circHelz caused cardiomyocyte injury in NMVCs by activating the NLRP3 inflammasome and inducing pyroptosis, while circHelz silencing reduced these effects induced by hypoxia. Furthermore, knockdown of circHelz remarkably attenuated NLRP3 expression, decreased myocardial infarct size, pyroptosis, inflammation, and increased cardiac function in vivo after MI. Overexpression of miR-133a-3p in cardiomyocytes greatly prevented pyroptosis in the presence of hypoxia or circHelz by targeting NLRP3 in NMVCs. Mechanistically, circHelz functioned as an endogenous sponge for miR-133a-3p via suppressing its activity. Overall, our results demonstrate that circHelz causes myocardial injury by triggering the NLRP3 inflammasome-mediated pro-inflammatory response and subsequent pyroptosis in cardiomyocytes by inhibiting miR-133a-3p function. Therefore, interfering with circHelz/miR133a-3p/NLRP3 axis might be a promising therapeutic approach for ischemic cardiac diseases.