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A circular transcript of ncx1 gene mediates ischemic myocardial injury by targeting miR-133a-3p.

ABSTRACT: Non-coding RNAs (ncRNAs) are considered major players in physiological and pathological processes based on their versatile regulatory roles in different diseases including cardiovascular disease. Circular RNAs (circRNAs), a newly discovered class of RNAs, constitute a substantial fraction of the mammalian transcriptome and are abundantly expressed in the cardiovascular system. However, the regulatory functions of these circRNAs in ischemic cardiac disease remain largely unknown. Here, we investigated the role of a circRNA transcribed from the sodium/calcium exchanger 1 (ncx1) gene, named circNCX1, in oxidative stress-induced cardiomyocyte apoptosis during ischemic myocardial injury. Methods: Divergent polymerase chain reaction (PCR) was conducted to amplify the circRNA. The circular structure of circNCX1 was verified by Sanger sequencing and RNase R digestion. The subcellular localization of circNCX1 was detected by fluorescence in situ hybridization (FISH). To test the expression pattern and function of circNCX1 during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with H₂O₂ or hypoxia-reoxygenation (H/R). Mechanistically, the interaction of circNCX1 with miRNA was examined by AGO2-IP and RNA pull-down assays. The regulatory role of circNCX1 in target gene expression was tested by western blot and luciferase reporter assays. At the animal level, we constructed a myocardial ischemia-reperfusion (I/R) mouse model to analyze the effect of circNCX1 on heart function, cardiomyocyte apoptosis and cardiac remodeling. Results: circNCX1 was increased in response to reactive oxygen species (ROS) and promotes cardiomyocyte apoptosis by acting as an endogenous miR-133a-3p sponge. Due to competitive binding of circNCX1 to miR-133a-3p, the suppressive activity of pro-apoptotic gene cell death-inducing protein (CDIP1) by miR-133a-3p was reduced. Knockdown of circNCX1 in murine cardiomyocytes and heart tissues reduced the levels of CDIP1 and attenuated the apoptosis and I/R injury. Conclusions: Our findings reveal a novel regulatory pathway that comprises circNCX1, miR-133a-3p and CDIP1, that is involved in cardiomyocyte apoptosis. This pathway may serve as a potential therapeutic avenue for ischemic heart diseases.

SUBMITTER: Li M

PROVIDER: S-EPMC6299442 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A circular transcript of <i>ncx1</i> gene mediates ischemic myocardial injury by targeting miR-133a-3p.

Li Mengyang M Ding Wei W Tariq Muhammad Akram MA Chang Wenguang W Zhang Xuejuan X Xu Wenhua W Hou Lin L Wang Yifei Y Wang Jianxun J

Theranostics 20181112 21

Non-coding RNAs (ncRNAs) are considered major players in physiological and pathological processes based on their versatile regulatory roles in different diseases including cardiovascular disease. Circular RNAs (circRNAs), a newly discovered class of RNAs, constitute a substantial fraction of the mammalian transcriptome and are abundantly expressed in the cardiovascular system. However, the regulatory functions of these circRNAs in ischemic cardiac disease remain largely unknown. Here, we investi ...[more]

PMID: 30613267

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Project description:Myocarditis (MC) is a common, potentially life-threatening inflammatory disease of the myocardium. A growing body of evidence has shown that mitogen-activated protein kinase 14 (MAPK14) participates in the pathogenesis of MC. However, the upstream regulators of MAPK14 remain enigmatic. Circular RNAs (circRNAs) have been identified to play vital roles in the pathophysiology of cardiovascular diseases. Nevertheless, the clinical significance, biological function, and regulatory mechanisms of circRNAs in MC remain poorly understood. In this study, we determined a novel circRNA, circACSL1 (ID: hsa_circ_0071542), which was significantly upregulated in the acute phase of MC, and its dynamic change in expression was related to the progression of MC. We used lipopolysaccharide (LPS) to induce the inflammatory responses in the human cardiomyocytes (HCM) line for in vitro and in cellulo experiments. The pro-inflammatory factors (IL-1β, IL-6, and TNF-α), myocardial injury markers (cTnT, CKMB, and BNP), cell viability, and cell apoptosis were measured to evaluate the extent of myocardial inflammation and myocardial injury level. Functional experiments, including gain-of-function and loss-of-function, were then performed to investigate the pro-inflammatory roles of circACSL1. The results revealed that circACSL1 could aggravate inflammation, myocardial injury, and apoptosis in HCM. Mechanistically, circACSL1 acted as a sponge for miR-8055-binding sites to regulate the downstream target MAPK14 expression. Furthermore, overexpression of miR-8055 rescued the pro-inflammatory effects of circACSL1 on HCM, and the upregulation of MAPK14 induced by circACSL1 was attenuated by miR-8055 overexpression. Knockdown of circACSL1 or overexpression of miR-8055 reduced myocardial inflammation and myocardial injury level and these effects were rescued by overexpression of MAPK14. In summary, our study demonstrated that circACSL1 could aggravate myocardial inflammation and myocardial injury through competitive absorption of miR-8055, thereby upregulating MAPK14 expression. Moreover, circACSL1 may represent a potential novel biomarker for the precise diagnosis of MC and offer a promising therapeutic target for MC treatment.