Poly(ADP-ribose) Polymerase (PARP) is Critically Involved in Liver Ischemia/Reperfusion-injury

Area of Science:

• Biochemistry
• Cell Biology
• Hepatology

Background:

• Poly(ADP-ribose) polymerase (PARP) is a DNA-repair enzyme activated by genomic stress.
• PARP is activated in liver ischemia following surgical resection.
• The role of PARP in post-ischemic liver injury remains unclear.

Purpose of the Study:

• To investigate the impact of PARP on liver injury induced by hypoxia/ischemia in mice.
• To elucidate the mechanisms of PARP-mediated cell death in hepatocytes.

Main Methods:

• Utilized a specific PARP inhibitor (PJ34) and a pan-caspase inhibitor (z-VAD-fmk).
• Assessed cell death, caspase activity, and PAR production under hypoxia/reoxygenation (H/R).
• Examined nuclear translocation of apoptosis-inducing factor (AIF) and RIP1-RIP3 interaction.
• Evaluated liver injury markers (AST, ALT, LDH) and necrosis in mouse models of ischemia/reperfusion.

Main Results:

• PARP inhibition (PJ34) protected against H/R-induced cell death, independently of caspase activity.
• H/R-induced cell death was redox-dependent, involving PARP activation.
• PARP inhibition suppressed parthanatos and necroptosis markers (AIF translocation, RIP1-RIP3 interaction).
• PJ34 reduced liver injury markers and necrosis in vivo, similar to antioxidants and caspase inhibitors.

Conclusions:

• PARP activation by ischemia/oxidative stress contributes to post-ischemic liver injury via parthanatos and necroptosis.
• PARP inhibition shows promise as a therapeutic strategy for post-ischemic liver injury.