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Upregulation of PTPN1 aggravates endotoxemia-induced cardiac dysfunction through inhibiting mitophagy

Qixiang Song1, Heng Ma1, Lili Zhu1

  • 1Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.

International Immunopharmacology
|December 3, 2023
PubMed
Abstract

Insights

Protein tyrosine phosphatase non-receptor type 1 (PTPN1) worsens sepsis-induced heart dysfunction by blocking mitophagy. Inhibiting PTPN1 may treat endotoxemia by restoring mitophagy and cardiac function.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Biology
  • Sepsis Pathophysiology

Background:

  • Sepsis can cause cardiac dysfunction and mitochondrial damage.
  • Mitophagy, the selective degradation of damaged mitochondria, plays a protective role.
  • The role of protein tyrosine phosphatase non-receptor type 1 (PTPN1) in sepsis-induced mitophagy is unclear.

Purpose of the Study:

  • To investigate PTPN1's role in mitophagy during sepsis.
  • To elucidate the mechanisms underlying PTPN1's effect on mitophagy.
  • To evaluate PTPN1 inhibitors as a therapy for endotoxemia-induced cardiac dysfunction.

Main Methods:

  • Endotoxemia model induced by lipopolysaccharide (LPS) in mice.
  • Evaluation of PTPN1 inhibitor Claramine (CLA) efficacy.
  • Assessment of mitochondrial function, mitophagy markers, and protein expression.
  • In vitro studies using H9c2 cardiomyocytes and STAT3 pathway analysis.

Main Results:

  • CLA treatment improved cardiac function and mitochondrial health in endotoxemic mice.
  • PTPN1 upregulation impaired mitophagy and worsened mitochondrial injury in cardiomyocytes.
  • PTPN1 interacted with STAT3, reducing its phosphorylation and inhibiting PINK1/PRKN transcription.
  • STAT3 directly regulated PINK1 and PRKN transcription via promoter binding.

Conclusions:

  • PTPN1 exacerbates cardiac dysfunction in endotoxemia by inhibiting mitophagy.
  • This inhibition occurs via STAT3 dephosphorylation and reduced PINK1/PRKN transcription.
  • Targeting PTPN1 offers a potential therapeutic strategy for sepsis-induced cardiac dysfunction.
Keywords:
Cardiac DysfunctionEndotoxemiaMitophagyPTPN1STAT3

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