CircHelz activates NLRP3 inflammasome to promote myocardial injury by sponging miR-133a-3p in mouse ischemic heart

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.

Automated summary

The study revealed that circHelz, a circRNA transcribed from the Helz gene, is significantly upregulated in ischemic myocardium and cardiomyocytes exposed to hypoxia. The overexpression of circHelz triggers NLRP3 inflammasome activation and pyroptosis, while silencing circHelz reduces these effects. Additionally, circHelz knockdown attenuates inflammasome expression, reduces myocardial injury and improves cardiac function after MI. Overexpression of miR-133a-3p prevents pyroptosis by targeting NLRP3, and circHelz functions as a sponge for miR-133a-3p. Ultimately, interfering with the circHelz/miR133a-3p/NLRP3 axis may be a promising therapeutic strategy for ischemic cardiac diseases.