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Circular RNA_101237 mediates anoxia/reoxygenation injury by targeting let?7a?5p/IGF2BP3 in cardiomyocytes.

ABSTRACT: Circular RNAs (circRNAs) serve important roles in cardiovascular diseases, including myocardial infarction. However, the mechanisms underlying the roles of circRNAs in cardiomyocyte death induced by anoxia/reoxygenation (A/R) are not fully understood. In the present study, the roles of circRNA_101237 and let?7a?5p in cardiomyocyte death induced by A/R injury were investigated. It was identified that circRNA_101237 was induced by A/R injury in a time?dependent manner and that circRNA_101237 knockdown protected cardiomyocytes from A/R?mediated apoptosis. Additional mechanistic studies revealed that circRNA_101237 served as a sponge for let?7a?5p, subsequently regulating insulin?like growth factor 2 mRNA?binding protein 3 (IGF2BP3)?dependent autophagy. IGF2BP3 downregulation decreased the levels of apoptosis and inhibited autophagy induced by A/R challenge in primary cardiomyocytes. These results identified circRNA_101237 as a novel circRNA that regulates cardiomyocyte death and autophagy, and demonstrated that the circRNA?101237/let?7a?5p/IGF2BP3 axis, which serves as a regulator of cardiomyocyte death, may be a potential therapeutic target for the management of cardiovascular diseases.

SUBMITTER: Gan J

PROVIDER: S-EPMC6984805 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Circular RNA_101237 mediates anoxia/reoxygenation injury by targeting let‑7a‑5p/IGF2BP3 in cardiomyocytes.

Gan Jianting J Yuan Jun J Liu Yu Y Lu Zhengde Z Xue Yan Y Shi Lei L Zeng Huayuan H

International journal of molecular medicine 20191223 2

Circular RNAs (circRNAs) serve important roles in cardiovascular diseases, including myocardial infarction. However, the mechanisms underlying the roles of circRNAs in cardiomyocyte death induced by anoxia/reoxygenation (A/R) are not fully understood. In the present study, the roles of circRNA_101237 and let‑7a‑5p in cardiomyocyte death induced by A/R injury were investigated. It was identified that circRNA_101237 was induced by A/R injury in a time‑dependent manner and that circRNA_101237 knock ...[more]

PMID: 31894303

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Project description:Background:Constitutive nuclear factor kappa B (NF?B) activation has been shown to exacerbate during myocardial ischemia/reperfusion (I/R) injury. We recently showed that miR-181c-5p exacerbated cardiomyocytes injury and apoptosis by directly targeting the 3'-untranslated region of protein tyrosine phosphatase nonreceptor type 4 (PTPN4). However, whether miR-181c-5p mediates cardiac I/R injury through NF?B-mediated inflammation is unknown. Thus, the present study aimed to investigate the role of miR-181c-5p during myocardial I/R injury and explore its mechanism in relation to inflammation in H9C2 cardiomyocytes. Methods and Results:In hypoxia/reoxygenation (H/R, 6?h hypoxia followed by 6?h reoxygenation)-stimulated H9C2 cardiomyocytes or postischemic myocardium of rat, the expression of miR-181c-5p was significantly upregulated, which was concomitant increased NF?B activity when compared to the nonhypoxic or nonischemic control groups. This is indicative that miR-181c-5p may be involved in NF?B-mediated inflammation during myocardial I/R injury. To investigate the potential role of miR-181c-5p in H/R-induced cell inflammation and injury, H9C2 cardiomyocytes were transfected with the miR-181c-5p agomir. Overexpression of miR-181c-5p significantly aggravated H/R-induced cell injury (increased lactate dehydrogenase (LDH) level) and exacerbated NF?B-mediated inflammation (greater phosphorylation and degradation of I?B?, phosphorylation of p65, and increased levels of proinflammatory cytokines tumor necrosis factor ? (TNF?), interleukin (IL)-6, and IL-1?). In contrast, inhibition of miR-181c-5p by its antagomir transfection in vitro had the opposite effect. Furthermore, overexpression of miR-181c-5p significantly enhanced lipopolysaccharide-induced NF?B signalling. Additionally, knockdown of PTPN4, the direct target of miR-181c-5p, significantly aggravated H/R-induced phosphorylation and degradation of I?B?, phosphorylation of p65, and the levels of proinflammatory cytokines. PTPN4 knockdown also cancelled miR-181c-5p antagomir mediated anti-inflammatory effects in H9C2 cardiomyocytes during H/R injury. Conclusions:It is concluded that miR-181c-5p may exacerbate myocardial I/R injury and NF?B-mediated inflammation via PTPN4, and that targeting miR-181c-5p/PTPN4/NF?B signalling may represent a novel strategy to combat myocardial I/R injury.

Dataset Information

Circular RNA_101237 mediates anoxia/reoxygenation injury by targeting let?7a?5p/IGF2BP3 in cardiomyocytes.

Publications

Circular RNA_101237 mediates anoxia/reoxygenation injury by targeting let‑7a‑5p/IGF2BP3 in cardiomyocytes.

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