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PIAS1 impedes vascular endothelial injury and atherosclerotic plaque formation in diabetes by blocking the RUNX3/TSP-1 axis

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Abstract

The protein PIAS1 functions as a type of ubiquitin-protease, which is known to play an important regulatory role in various diseases, including cardiovascular diseases and cancers. Its mechanism of action primarily revolves around regulating the transcription, translation, and modification of target proteins. This study investigates role and mechanism of PIAS1 in the RUNX3/TSP-1 axis and confirms its therapeutic effects on diabetes-related complications in animal models. A diabetic vascular injury was induced in human umbilical vein endothelial cells (HUVECs) by stimulation with H2O2 and advanced glycation end product (AGE), and a streptozotocin (STZ)-induced mouse model of diabetes was constructed, followed by detection of endogenous PIAS1 expression and SUMOylation level of RUNX3. Effects of PIAS1 concerning RUNX3 and TSP-1 on the HUVEC apoptosis and inflammation were evaluated using the ectopic expression experiments. Down-regulated PIAS1 expression and SUMOylation level of RUNX3 were identified in the H2O2- and AGE-induced HUVEC model of diabetic vascular injury and STZ-induced mouse models of diabetes. PIAS1 promoted the SUMOylation of RUNX3 at the K148 site of RUNX3. PIAS1-mediated SUMOylation of RUNX3 reduced RUNX3 transactivation activity, weakened the binding of RUNX3 to the promoter region of TSP-1, and caused downregulation of TSP-1 expression. PIASI decreased the expression of TSP-1 by inhibiting H2O2- and AGE-induced RUNX3 de-SUMOylation, thereby arresting the inflammatory response and apoptosis of HUVECs. Besides, PIAS1 reduced vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes by inhibiting the RUNX3/TSP-1 axis. Our study proved that PIAS1 suppressed vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes via the RUNX3/TSP-1 axis.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge and appreciate our colleagues’ valuable efforts and comments on this paper.

Funding

This study is supported by the National Natural Science Foundation of China (No. 81273200).

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  1. Qingsong Jin and Tiantian Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People’s Republic of China

    Qingsong Jin, Tiantian Zhao, Liangyan Lin, Xiaoyan Yao, Yaqin Teng, Dongdong Zhang & Yongjun Jin

  2. Department of Pharmacology, School of Basic Medical Sciences, Binzhou Medical University, No. 522, Huanghe Third Road, Binzhou, 264003, People’s Republic of China

    Meizi Yang

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Contributions

QJ, TZ, and LL wrote the paper and conceived and designed the experiments. XY, YT, and DZ analyzed the data. YJ and MY collected and provided the sample for this study. All authors have read and approved the final submitted manuscript.

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Correspondence to Yongjun Jin or Meizi Yang.

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The animal study was approved by the Institutional Animal Care and Use Committee (IACUC) of Yantai Affiliated Hospital of Binzhou Medical College (IRB2022-0043). Animal experiments were strictly designed and implemented according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

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Supplementary Fig. S1 The SUMOylation site information of RUNX3 (EPS 687 KB)

13577_2023_952_MOESM2_ESM.eps

Supplementary Fig. S2 TUNEL staining test for apoptosis of cells in each group after stimulation by H2O2 or AGE. A: TUNEL staining test for apoptosis of cells in each group after H2O2 stimulation (400×); B: TUNEL staining test for apoptosis of cells in each group after AGE stimulation (400×). The experiment was repeated three times (EPS 2628 KB)

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Jin, Q., Zhao, T., Lin, L. et al. PIAS1 impedes vascular endothelial injury and atherosclerotic plaque formation in diabetes by blocking the RUNX3/TSP-1 axis. Human Cell 36, 1915–1927 (2023). https://doi.org/10.1007/s13577-023-00952-0

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