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Circ-LTBP1 is involved in doxorubicin-induced intracellular toxicity in cardiomyocytes via miR-107/ADCY1 signal

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Abstract

Although doxorubicin (DOX) is a broad-spectrum and anthracycline chemotherapeutic agent, cardiotoxicity limits its clinical application. Therefore, it is meant to prevent the clinical side effects of DOX. Human cardiomyocyte-like AC16 cells were treated with DOX to induce intracellular toxicity. AC16 cell viability was determined by Cell Counting Kit 8 and 5-ethynyl-2′-deoxyuridine assays. The tumor necrosis factor-α and interleukin-6 abundances were quantified by matched kits. The apoptosis rate was measured by flow cytometry. Western blot analysis was conducted to measure the protein expression levels in AC16 cells. Oxidative stress was analyzed by measuring superoxide dismutase and malondialdehyde production. The quantitative real-time polymerase chain reaction was conducted to assess the expression levels of circ-latent transforming growth factor-beta binding protein-1 (circ-LTBP1), microRNA-107 (miR-107), and Adenylate cyclase 1 (ADCY1) expression in AC16 cells. The interaction relationship among circ-LTBP1, miR-107, and ADCY1 was verified by dual-luciferase reporter and RNA immunoprecipitation assays. As a result, treatment with DOX induced the proliferation inhibition, inflammation, apoptosis, and oxidative stress in AC16 cells, which were rescued by circ-LTBP1 inhibition or miR-107 upregulation. MiR-107 was confirmed as a target of circ-LTBP1, and inhibition of circ-LTBP1-mediated effects on DOX-stimulated cells were abolished by downregulation of miR-107. Circ-LTBP1 mediated ADCY1 expression by sponging miR-107 in AC16 cells. The upregulation of miR-107 increased cell proliferation and inhibited inflammation, apoptosis, and oxidative stress in DOX-stimulated cells through downregulation of ADCY1. Circ-LTBP1 was found to enhance DOX-induced effects on proliferation inhibition, inflammation, apoptosis, and oxidative stress in AC16 cells through competitively sponging miR-107 and elevating ADCY1.

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Abbreviations

DOX:

Doxorubicin

EdU:

Ethynyl-2′-deoxyuridine

TGF:

Transforming growth factor

miR-107:

MicroRNA-107

ADCY1:

Adenylate cyclase 1

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Authors and Affiliations

  1. Department Integrated Medical Services Section, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China

    Chunxia Li, Lihui Zhang, Xingpeng Bu, Jinyu Wang & Li Li

  2. Department of Cardiology, Second Hospital of Shanxi Medical University, 382 Wuyi Road, Xinghualing, Taiyuan, 030000, Shanxi, China

    Zhiming Yang

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  1. Chunxia Li
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  2. Lihui Zhang
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  3. Xingpeng Bu
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  4. Jinyu Wang
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  5. Li Li
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Contributions

LZ and XB designed and performed the research; JW, LL and ZY analyzed the data; CL wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zhiming Yang.

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The research has been carried out in accordance with the World Medical Association Declaration of Helsinki, and that all subjects provided written informed consent.

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Written informed consents were obtained from all participants and this study was permitted by the Ethics Committee of Shanxi Bethune Hospital, Shanxi Medical University Third Hospital.

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Li, C., Zhang, L., Bu, X. et al. Circ-LTBP1 is involved in doxorubicin-induced intracellular toxicity in cardiomyocytes via miR-107/ADCY1 signal. Mol Cell Biochem 477, 1127–1138 (2022). https://doi.org/10.1007/s11010-022-04360-0

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