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/miR-133a-3p/NLRP3 axis might be a promising therapeutic approach for ischemic cardiac diseases.

众所周知，心肌梗塞 (MI) 诱导的 NLRP3 炎性体激活会通过引起心脏炎症和细胞焦亡来加重心肌损伤和心脏功能障碍。环状 RNA (circRNA) 已被证明在心血管疾病中发挥关键作用。然而，circRNAs 在调节心脏炎症反应和心肌细胞焦亡方面的功能和机制仍然很大程度上未知。我们发现 circHelz 是一种从具有锌指 (Helz) 基因的解旋酶转录的新型 circRNA，在 MI 小鼠的缺血性心肌和暴露于缺氧的新生小鼠心室心肌细胞 (NMVC) 中均显着上调。circHelz 的过表达通过激活 NLRP3 炎性体并诱导细胞焦亡导致 NMVC 中的心肌细胞损伤，而circHelz沉默减少了缺氧引起的这些影响。此外，circHelz 的敲低显着减弱了 NLRP3 的表达，减少了心肌梗塞面积、细胞焦亡、炎症和增加心脏功能心肌梗死后的体内。miR-133a-3p 在心肌细胞中的过表达通过靶向 NMVC 中的 NLRP3 极大地防止了缺氧或 circHelz 存在下的细胞焦亡。从机制上讲，circHelz通过抑制miR-133a-3p 的活性作为内源性海绵发挥作用。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 炎性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/miR-133a-3p/NLRP3 轴可能是缺血性心脏病的一种有前途的治疗方法。