1. Academic Validation
  2. Oxidized DJ-1 activates the p-IKK/NF-κB/Beclin1 pathway by binding PTEN to induce autophagy and exacerbate myocardial ischemia-reperfusion injury

Oxidized DJ-1 activates the p-IKK/NF-κB/Beclin1 pathway by binding PTEN to induce autophagy and exacerbate myocardial ischemia-reperfusion injury

  • Eur J Pharmacol. 2024 Mar 18:971:176496. doi: 10.1016/j.ejphar.2024.176496.
Huiru Liu 1 Xueying Wang 2 Kang He 1 Zihan Chen 3 Xiaoqi Li 1 Jianmin Ren 1 Xiaoyan Zhao 4 Song Liu 1 Tingting Zhou 4 Heping Chen 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
  • 2 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China; Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330004, PR China.
  • 3 Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi, 330006, PR China.
  • 4 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China; Affiliated Hospital of Jining Medical University, Jining, Shandong, 272000, PR China.
  • 5 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, PR China. Electronic address: chenheping69@hotmail.com.
Abstract

Patients with myocardial infarction have a much worse prognosis when they have myocardial ischemia-reperfusion (I/R) injury. Further research into the molecular basis of myocardial I/R injury is therefore urgently needed, as well as the identification of novel therapeutic targets and linkages to interventions. Three cysteine residues are present in DJ-1 at Amino acids 46, 53, and 106 sites, with the cysteine at position 106 being the most oxidation-prone. This study sought to understand how oxidized DJ-1(C106) contributes to myocardial I/R damage. Rats' left anterior descending branches were tied off to establish a myocardial I/R model in vivo. A myocardial I/R model in vitro was established via anoxia/reoxygenation (A/R) of H9c2 cells. The results showed that Autophagy increased after I/R, accompanied by the increased expression of oxidized DJ-1 (ox-DJ-1). In contrast, after pretreatment with NAC (N-acetylcysteine, a ROS scavenger) or Comp-23 (Compound-23, a specific antioxidant binding to the C106 site of DJ-1), the levels of ox-DJ-1, Autophagy and LDH release decreased, and cell survival rate increased. Furthermore, the inhibition of interaction between ox-DJ-1 and PTEN could increase PTEN Phosphatase activity, inhibit the p-IKK/NF-κB/Beclin1 pathway, reduce injurious Autophagy, and alleviate A/R injury. However, BA (Betulinic acid, a NF-κB Agonist) was able to reverse the protective effects produced by Comp-23 pretreatment. In conclusion, ox-DJ-1 could activate detrimental Autophagy through the PTEN/p-IKK/NF-κB/Beclin1 pathway and exacerbate myocardial I/R injury.

Keywords

Autophagy; Myocardial I/R injury; PTEN/p-IKK/NF-κB/Beclin1; ox-DJ-1.

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