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MicroRNA-197-3p mediates damage to human coronary artery endothelial cells via targeting TIMP3 in Kawasaki disease

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Abstract

Kawasaki disease (KD) causes cardiovascular system injury in children. However, the pathogenic mechanisms of KD have not been well defined. Recently, strong correlation between aberrant microRNAs and KD nosogenesis has been revealed. A role of microRNA-197-3p (miR-197-3p) in the pathogenesis of KD is identified in the present study. Cell proliferation assay showed human coronary artery endothelial cells (HCAECs) were suppressed by serum from KD patients, which was correlated with high levels of miR-197-3p in both KD serum and HCAECs cultured with KD serum. The inhibition of HCAECs by miR-197-3p was confirmed by cells expressing miR-197-3p mimic and miR-197-3p inhibitor. Comparative proteomics analysis and Ingenuity Pathway Analysis (IPA) revealed TIMP3 as a potential target of miR-197-3p, which was demonstrated by western blot and dual-luciferase reporter assays. Subsequently, by detecting the endothelium damage markers THBS1, VWF, and HSPG2, the role of miR-197-3p/TIMP3 in KD-induced damage to HCAECs was confirmed, which was further validated by a KD mouse model in vivo. The expressions of miR-197-3p and its target, TIMP3, are dramatically variational in KD serum and HCAECs cultured with KD serum. Increased miR-197-3p induces HCAECs abnormal by restraining TIMP3 expression directly. Hence, dysregulation of miR-197-3p/TIMP3 expression in HCAECs may be an important mechanism in cardiovascular endothelium injury in KD patients, which offers a feasible therapeutic target for KD treatment.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81973341), Science and Technology Program of Guangzhou (Grant No. 202002030010), and the Fundamental Research Funds for the Central Universities (Grant No. 21620426).

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    Authors and Affiliations

    1. Institute of Mass Spectrometer and Atmospheric Environment, Jinan University, Guangzhou, 510632, China

      Chaowu Liu

    2. Guangdong Institute of Microbiology, Guangdong Academy of Sciences, State Key Laboratory of Applied Microbiology Southern China, Guangzhou, 510070, Guangdong, China

      Chaowu Liu

    3. Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, Guangdong, China

      Deguang Yang

    4. Guangdong Province Engineering Research Center for Antibody Drug and Immunoassay, Colleges of Life Science and Technology, Jinan University, Guangzhou, 510632, Guangdong, China

      Hong Wang

    5. MOE Key Laboratory of Tumor Molecular Biology, Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China

      Shengwei Hu & Qi Qi

    6. Department of Pediatric Cardiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China

      Xiaofei Xie & Li Zhang

    7. Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China

      Hongling Jia

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    Contributions

    JH and QQ conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. LC, YD and WH designed and performed most of the experiments and analyzed the data. HS, XX and ZL carried out the western blot.

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    Correspondence to Hongling Jia or Qi Qi.

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    Ethical approval

    This study with human serum was approved by with the Ethics Committees at First Affiliated Hospital of Jinan University. The animal care and experimental procedures were approved by the Animal Experimental Committee of Jinan University.

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    Chaowu Liu, Deguang Yang, and Hong Wang have contributed equally to this study.

    Supplementary Information

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    11010_2021_4238_MOESM1_ESM.tif

    Supplementary figure 1. Transfection efficiency testing in HCAECs. Cells were transfected with GFP expression plasmids using Lipofectamine 3000. Following 40 hours transfection, the GFP expression was confirmed by fluorescence microscope. Supplementary file1 (TIF 4336 kb)

    11010_2021_4238_MOESM2_ESM.tif

    Supplementary figure 2. KD mouse model constructed by LCWE. A. LCWE-induced coronary arteritis and myocardial inflammation in mice at days 14 post LCWE injection. No pathological changes occurred in the control mice injected with vehicle. However, LCWE-injected mice displayed pronounced coronary and myocardial inflammation associated with acute cellular infiltration. B-D. The levels of TNF-α (B), IL-1β (C), and IL-6 (D) were significantly elevated in the serum of KD mice compared with the control mice. Supplementary file2 (TIF 10108 kb)

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    Liu, C., Yang, D., Wang, H. et al. MicroRNA-197-3p mediates damage to human coronary artery endothelial cells via targeting TIMP3 in Kawasaki disease. Mol Cell Biochem 476, 4245–4263 (2021). https://doi.org/10.1007/s11010-021-04238-7

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