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Hyperglycemia-Induced Overexpression of PH Domain Leucine-Rich Repeat Protein Phosphatase 1 (PHLPP1) Compromises the Cardioprotective Effect of Ischemic Postconditioning Via Modulation of the Akt/Mst1 Pathway Signaling

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Abstract

Purpose

Ischemic postconditioning (IPostC) alleviates myocardial ischemia/reperfusion (IR) injury, but the protective effect is lost during diabetes. PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is able to inactivate Akt. Our previous study found that PHLPP1 expression was upregulated in diabetic hearts. We presumed that the attenuation of myocardial injury by IPostC might be hindered by PHLPP1 overexpression in diabetic animals.

Methods and results

Nondiabetic and diabetic mice were subjected to 45 min of ischemia followed by 2 h of reperfusion with or without IPostC. H9c2 cells were exposed to normal or high glucose and were subjected to 4 h of hypoxia followed by 4 h of reoxygenation with or without hypoxic postconditioning (HPostC). IPostC attenuated postischemic infarction, apoptosis, creatine kinase-MB, and oxidative stress, which were accompanied by increased p-Akt and decreased PHLPP1 expression and p-Mst1 in nondiabetic but not in diabetic mice. PHLPP1 knockdown or an Mst1 inhibitor reduced hypoxia/reoxygenation (HR)-induced cardiomyocyte damage in H9c2 cells exposed to normal glucose, but the effect was abolished by a PI3K/Akt inhibitor. HPostC attenuated HR-induced cardiomyocyte injury and oxidative stress accompanied by increased p-Akt as well as decreased PHLPP1 expression and p-Mst1 in H9c2 cells exposed to normal glucose but not high glucose. In addition, HPostC in combination with PHLPP1 knockdown or PHLPP1 knockdown alone reduced cell death and oxidative stress in H9c2 cells exposed to high glucose, which was hindered by PI3K/Akt inhibitor.

Conclusion

IPostC prevented myocardial IR injury partly through PHLPP1/Akt/Mst1 signaling, and abnormalities in this pathway may be responsible for the loss of IPostC cardioprotection in diabetes.

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Data Availability

The data used to support the findings of this study are included within the article.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (NO. 81800721), the Natural Science Foundation of Huai’an (HAB201802), and the Postdoctoral Foundation of China and Jiangsu (2020M671387, 2020Z393).

Author information

Author notes

  1. Yun Qiu and Yuming Meng contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency Medicine, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, 223300, Jiangsu, China

    Yun Qiu, Yuming Meng, Yajuan Jia, Xuemei Lang, Hongmei Zhao, Hong Sun & Sumin Gao

  2. Department of Neurosurgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, 223300, Jiangsu, China

    Lianshu Ding

  3. Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China

    Tingting Wang

Authors
  1. Yun Qiu
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Contributions

SG, HS, YQ, and YM conceived and designed the experiments; YQ, YM, YJ, and XL performed the experiments; YQ, YM, YJ, XL, SG, and HS analyzed the data; and YQ, YM, HZ, SG, LD, TW, and HS contributed to discussion and wrote the paper. All the authors read and approved the final paper.

Corresponding authors

Correspondence to Hong Sun or Sumin Gao.

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The care of animals and all animal experiments were implemented after being reviewed and approved by the Institutional Animal Use and Care Committee at Nanjing Medical University.

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Qiu, Y., Meng, Y., Jia, Y. et al. Hyperglycemia-Induced Overexpression of PH Domain Leucine-Rich Repeat Protein Phosphatase 1 (PHLPP1) Compromises the Cardioprotective Effect of Ischemic Postconditioning Via Modulation of the Akt/Mst1 Pathway Signaling. Cardiovasc Drugs Ther 37, 1087–1101 (2023). https://doi.org/10.1007/s10557-022-07349-5

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