2. Academic Validation
  3. 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

  • J Mol Cell Cardiol. 2021 Sep;158:128-139. doi: 10.1016/j.yjmcc.2021.05.010.
Yu Bian 1,  Ping Pang 2,  Xin Li 3,  Shuting Yu 3,  Xiuzhu Wang 3,  Kuiwu Liu 3,  Jiaming Ju 4,  Han Wu 3,  Yuelin Gao 3,  Qian Liu 3,  Yingqiong Jia 3,  Zhezhe Qu 3,  Xiaoqian Bi 3,  Zhongting Mei 3,  Xinda Yin 3,  Ning Wang 5,  Weijie Du 6,  Baofeng Yang 7
Affiliations

Affiliations

  • 1 Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, PR China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang 150081, PR China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
  • 2 Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.
  • 3 Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, PR China.
  • 4 Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
  • 5 Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, PR China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang 150081, PR China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. Electronic address: wangning@ems.hrbmu.edu.cn.
  • 6 Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, PR China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang 150081, PR China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. Electronic address: duweijie@hrbmu.edu.cn.
  • 7 Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, PR China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang 150081, PR China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, PR China; Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China. Electronic address: yangbf@ems.hrbmu.edu.cn.
PMID: 34043986 DOI: 10.1016/j.yjmcc.2021.05.010
Abstract

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.

Keywords

CircHelz; Myocardial infarction; NLRP3 inflammasome; Pyroptosis; miR-133a-3p.

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