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Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury

Zheng-Hao Zhang1, Zi-Guan Zhang1, Min-Wei Chen1

  • 1Department of Cardiology, Xiamen Key Laboratory of Cardiac Electrophysiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

Oxidative Medicine and Cellular Longevity
|July 5, 2022
PubMed

Insights

Gasdermin D (GSDMD) plays a dual role in heart reperfusion injury. Inhibiting GSDMD initially protects the heart but later worsens injury by promoting apoptosis.

Area of Science:

  • Cardiovascular Biology
  • Cell Death Mechanisms
  • Molecular Medicine

Background:

  • Myocardial ischemia-reperfusion (I/R) injury involves complex cell death pathways, including apoptosis and pyroptosis.
  • Gasdermin D (GSDMD) is recognized as a key executioner protein in pyroptosis, but its broader role in I/R is not fully understood.

Purpose of the Study:

  • To investigate the role of GSDMD in regulating cardiomyocyte viability during myocardial I/R.
  • To elucidate the mechanisms by which GSDMD influences different cell death modalities in I/R.

Main Methods:

  • Analysis of GSDMD and GSDMD-N expression in a mouse model of myocardial I/R.
  • Assessment of cardiac function and injury in GSDMD knockout mice during acute and chronic I/R.
  • Investigation of molecular pathways, including PARylation, NAD+, and ATP consumption, in GSDMD-deficient hearts.
  • Evaluation of the therapeutic effect of a PARP-1 inhibitor (PJ34).

Main Results:

  • GSDMD and its N-terminal fragment were significantly upregulated in I/R myocardium.
  • GSDMD knockout provided acute protection against I/R but exacerbated injury in the chronic phase.
  • GSDMD deficiency led to increased PARylation, NAD+ and ATP depletion, and subsequent cardiomyocyte apoptosis.
  • PJ34 treatment mitigated myocardial injury associated with GSDMD deficiency.

Conclusions:

  • GSDMD exhibits a multidirectional role in regulating cardiomyocyte death during I/R.
  • GSDMD inhibition can paradoxically activate PARylation and promote apoptosis, highlighting a novel mechanism.
  • These findings offer new insights into the pathophysiology of I/R injury and suggest potential therapeutic strategies targeting GSDMD.

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