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RP105 Attenuates Ischemia/Reperfusion-Induced Oxidative Stress in the Myocardium via Activation of the Lyn/Syk/STAT3 Signaling Pathway

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Abstract

Although our previous studies have established the crucial role of RP105 in myocardial ischemia/reperfusion injury (MI/RI), its involvement in regulating oxidative stress induced by MI/RI remains unclear. To investigate this, we conducted experiments using a rat model of ischemia/reperfusion (I/R) injury. Adenovirus carrying RP105 was injected apically at multiple points, and after 72 h, the left anterior descending coronary artery was ligated for 30 min followed by 2 h of reperfusion. In vitro experiments were performed on H9C2 cells, which were transfected with recombinant adenoviral vectors for 48 h, subjected to 4 h of hypoxia, and then reoxygenated for 2 h. We measured oxidative stress markers, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, as well as malondialdehyde (MDA) concentration, using a microplate reader. The fluorescence intensity of reactive oxygen species (ROS) in myocardial tissue was measured using a DHE probe. We also investigated the upstream and downstream components of the signal transducer and activator of transcription 3 (STAT3). Upregulation of RP105 increased SOD and GSH-Px activities, reduced MDA concentration, and inhibited ROS production in response to I/R injury in vivo and hypoxia reoxygenation (H/R) stimulation in vitro. The overexpression of RP105 led to a decrease in the myocardial enzyme LDH in serum and cell culture supernatant, as well as a reduction in infarct size. Additionally, left ventricular fraction (LVEF) and fractional shortening (LVFS) were improved in the RP105 overexpression group compared to the control. Upregulation of RP105 promoted the expression of Lyn and Syk and further activated STAT phosphorylation, which was blocked by PP2 (a Lyn inhibitor). Our findings suggest that RP105 can inhibit MI/RI-induced oxidative stress by activating STAT3 via the Lyn/Syk signaling pathway.

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DATA AVAILABILITY

No datasets were generated or analysed during the current study.

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Funding

The research described in this article was supported by the following grants: National Natural Science Foundation of China (82070372, 82170418, 82271618), Hubei Province’s Outstanding Medical Academic Leader Program; Natural Science Foundation of Hubei Province (2022CFA015); Science and Technology Innovation Platform of Hubei Province (2022DCC014); Key Research and Development Program of Hubei Province (2022BCE001); Hubei Provincial Health Commission Project (WJ2023M151); and Research Fund for Excellent Dissertation of China Three Gorges University (2021SSPY101).

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  1. Jian Yang, Yuhong Zhai, and Cuiyuan Huang contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yiling Road 183, Yichang, 443000, Hubei, China

    Jian Yang, Yuhong Zhai, Cuiyuan Huang, Zujin Xiang, Haiyin Liu, Jingyi Wu, Yifan Huang, Li Liu, Wenqiang Li, Wei Wang, Jun Yang & Jing Zhang

  2. Hubei Key Laboratory of Ischemic Cardiovascular Disease, Yichang, 443000, China

    Jian Yang, Yuhong Zhai, Cuiyuan Huang, Zujin Xiang, Haiyin Liu, Jingyi Wu, Yifan Huang, Li Liu, Wenqiang Li, Wei Wang, Jun Yang & Jing Zhang

  3. HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443000, China

    Jian Yang, Yuhong Zhai, Cuiyuan Huang, Zujin Xiang, Haiyin Liu, Jingyi Wu, Yifan Huang, Li Liu, Wenqiang Li, Wei Wang & Jing Zhang

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Contributions

Y.J, Z.YH. and H.CY. as co-first authors and were primarily responsible for analyzing the data and drafting the manuscript. Y.J. contributed ideas and designed the experimental process, while Z.J. guided the experimental operation and problem-solving. X.ZJ., L.HY., W.JY., H.YF., L.L., L.WQ., W.W. conducted the animal and cell experiments. All authors reviewed the manuscript.

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Correspondence to Jun Yang or Jing Zhang.

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This experiment was approved by the animal ethics committee of China Three Gorges University (NO.202205010W).

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Yang, J., Zhai, Y., Huang, C. et al. RP105 Attenuates Ischemia/Reperfusion-Induced Oxidative Stress in the Myocardium via Activation of the Lyn/Syk/STAT3 Signaling Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-01982-y

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