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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

iNOS/NO signaling regulates apoptosis induced by glycochenodeoxycholate in hepatocytes

Kewei Wang1, John J Brems, Richard L Gamelli

  • 1Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, United States. kewei_wang@rush.edu

Cellular Signalling
|June 23, 2011
PubMed

Insights

Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) signaling pathways modulate hepatocyte apoptosis. Low NO doses inhibit apoptosis via the iNOS/Akt/survivin axis, while high doses promote it through p38MAPK/CHOP activation.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • Toxic glycochenodeoxycholate (GCDC) induces hepatocyte apoptosis.
  • Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) show potential protective effects against GCDC-induced apoptosis.
  • The detailed molecular mechanisms of iNOS/NO in this process remain unclear.

Purpose of the Study:

  • To elucidate the function and underlying molecular mechanisms of iNOS/NO signaling in GCDC-induced hepatocyte apoptosis.
  • To investigate the dual role of exogenous NO in modulating apoptotic pathways.
  • To identify potential therapeutic targets for cholestatic liver disease.

Main Methods:

  • Induction of apoptosis using GCDC in primary rat hepatocytes.
  • Investigation of iNOS/NO signaling pathways, including the use of iNOS inhibitor 1400W.
  • Assessment of apoptosis via caspase-3 activity and TUNEL assay.
  • Administration of exogenous NO using donors like SNAP and SNP at varying concentrations.

Main Results:

  • Inhibition of iNOS (1400W) exacerbated GCDC-induced hepatocyte apoptosis.
  • Exogenous NO exhibited a dual role: low doses (SNAP/SNP) decreased apoptosis, while high doses increased it.
  • Low NO doses activated the iNOS/Akt/survivin pathway, inhibiting apoptosis.
  • High NO doses activated the p38MAPK/CHOP pathway, upregulated DR5, and suppressed survivin, promoting apoptosis.

Conclusions:

  • iNOS/NO signaling plays a complex, dose-dependent role in GCDC-induced hepatocyte apoptosis.
  • The iNOS/Akt/survivin and p38MAPK/CHOP pathways are key mediators of NO's dual effects.
  • Targeting these signaling pathways offers potential therapeutic strategies for cholestatic liver diseases.

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