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Nitric oxide suppresses the expression of Bcl-2 binding protein BNIP3 in hepatocytes

R Zamora1, L Alarcon, Y Vodovotz

  • 1Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA. zamorar@pitt.edu

The Journal of Biological Chemistry
|October 11, 2001
PubMed

Insights

Nitric oxide (NO) suppresses the expression of the pro-apoptotic gene BNIP3 in liver cells. This NO-mediated suppression, involving the soluble guanylyl cyclase/cyclic guanosine monophosphate pathway, may protect hepatocytes from apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) is a crucial signaling molecule regulating gene expression in the liver.
  • NO, particularly from inducible nitric-oxide synthase (iNOS), protects hepatocytes from apoptosis induced by TNF-α and actinomycin D.
  • Mechanisms of NO's protective effects involve both cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways.

Purpose of the Study:

  • To investigate whether NO regulates genes involved in apoptosis.
  • To identify specific genes whose expression is modulated by NO in hepatocytes.
  • To elucidate the role of NO in controlling hepatocyte apoptosis through gene expression regulation.

Main Methods:

  • Differential display-polymerase chain reaction (DD-PCR) was used to identify NO-regulated genes in hepatocytes from iNOS knockout mice.
  • Northern blot analysis was employed to confirm gene expression changes.
  • Hepatocytes were treated with an NO donor (S-nitroso-N-acetyl-dl-penicillamine) and an sGC inhibitor (ODQ) to assess pathway involvement.

Main Results:

  • DD-PCR identified a NO-suppressed gene fragment homologous to BNIP3, a pro-apoptotic protein.
  • Northern analysis confirmed that NO down-regulates BNIP3 expression in hepatocytes.
  • The NO-induced suppression of BNIP3 was reversed by the sGC inhibitor ODQ, indicating involvement of the sGC/cGMP pathway.

Conclusions:

  • NO suppresses the expression of the pro-apoptotic gene BNIP3 in hepatocytes.
  • This suppression is mediated, at least in part, through the soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) pathway.
  • Suppression of BNIP3 represents a novel mechanism by which NO may exert its anti-apoptotic effects in liver cells.

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