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Inhibition of Phosphoglycerate Mutase 5 Reduces Necroptosis in Rat Hearts Following Ischemia/Reperfusion Through Suppression of Dynamin-Related Protein 1

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Abstract

Purpose

Necroptosis is an important form of cell death following myocardial ischemia/reperfusion (I/R) and phosphoglycerate mutase 5 (PGAM5) functions as the convergent point for multiple necrosis pathways. This study aims to investigate whether inhibition of PGAM5 could reduce I/R-induced myocardial necroptosis and the underlying mechanisms.

Methods

The SD rat hearts (or H9c2 cells) were subjected to 1-h ischemia (or 10-h hypoxia) plus 3-h reperfusion (or 4-h reoxygenation) to establish the I/R (or H/R) injury model. The myocardial injury was assessed by the methods of biochemistry, H&E (hematoxylin and eosin), and PI/DAPI (propidium iodide/4′,6-diamidino-2-phenylindole) staining, respectively. Drug interventions or gene knockdown was used to verify the role of PGAM5 in I/R (or H/R)-induced myocardial necroptosis and possible mechanisms.

Results

The I/R-treated heart showed the injuries (increase in infarct size and creatine kinase release), upregulation of PGAM5, dynamin-related protein 1 (Drp1), p-Drp1-S616, and necroptosis-relevant proteins (RIPK1/RIPK3, receptor-interacting protein kinase 1/3; MLKL, mixed lineage kinase domain-like); these phenomena were attenuated by inhibition of PGAM5 or RIPK1. In H9c2 cells, H/R treatment elevated the levels of PGAM5, RIPK1, RIPK3, MLKL, Drp1, and p-Drp1-S616 and induced mitochondrial dysfunctions (elevation in mitochondrial membrane potential and ROS level) and cellular necrosis (increase in LDH release and the ratio of PI+/DAPI+ cells); these effects were blocked by inhibition or knockdown of PGAM5.

Conclusions

Inhibition of PGAM5 can reduce necroptosis in I/R-treated rat hearts through suppression of Drp1; there is a positive feedback between RIPK1 and PGAM5, and PGAM5 might serve as a novel therapeutic target for prevention of myocardial I/R injury.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81872873 to Jun Peng; No. 81573430 to Xiu-Ju Luo; No. 81703516 to Bin Liu).

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Author notes

  1. Lang She and Hua Tu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, No.110 Xiangya Road, Changsha, 410078, China

    Lang She, Hua Tu, Li-Jing Tang, Nian-Sheng Li & Jun Peng

  2. Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China

    Yin-Zhuang Zhang & Qi-Lin Ma

  3. Department of Laboratory Medicine, Xiangya Third Hospital, Central South University, Changsha, 410013, China

    Nian-Sheng Li & Xiu-Ju Luo

  4. Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China

    Bin Liu & Jun Peng

  5. Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, 77555-1083, USA

    Qingjie Li

Authors
  1. Lang She
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  2. Hua Tu
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Correspondence to Xiu-Ju Luo or Jun Peng.

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She, L., Tu, H., Zhang, YZ. et al. Inhibition of Phosphoglycerate Mutase 5 Reduces Necroptosis in Rat Hearts Following Ischemia/Reperfusion Through Suppression of Dynamin-Related Protein 1. Cardiovasc Drugs Ther 33, 13–23 (2019). https://doi.org/10.1007/s10557-018-06848-8

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