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Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-beta in fetal rat

Blanca Herrera1, Miguel M Murillo, Alberto Alvarez-Barrientos

  • 1Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.

Free Radical Biology & Medicine
|January 21, 2004
PubMed

Insights

Transforming growth factor-beta (TGF-beta) triggers oxidative stress in hepatocytes, leading to cell death. Early reactive oxygen species (ROS) production is primarily driven by NADPH oxidase, with mitochondrial complex I playing a secondary role.

Area of Science:

  • Hepatocyte biology
  • Oxidative stress mechanisms
  • Cell death pathways

Background:

  • Transforming growth factor-beta (TGF-beta) is a key regulator of cellular processes, including apoptosis.
  • Oxidative stress, characterized by an imbalance of reactive oxygen species (ROS), is implicated in TGF-beta-induced hepatocyte death.
  • Identifying the source of ROS is crucial for understanding TGF-beta's apoptotic signaling.

Purpose of the Study:

  • To pinpoint the cellular origin of early reactive oxygen species (ROS) generated by fetal rat hepatocytes upon TGF-beta stimulation.
  • To elucidate the specific ROS-producing systems involved in TGF-beta-mediated hepatocyte apoptosis.

Main Methods:

  • Utilized specific inhibitors targeting various ROS-producing systems (NADPH oxidase, mitochondrial complex I, cytochrome P450, cyclooxygenase, xanthine oxidase).
  • Assessed the impact of inhibitors on ROS production, caspase-3 activation, and cell death in response to TGF-beta.
  • Investigated potential mechanisms including inducible NADPH oxidase-like systems and antioxidant gene regulation.

Main Results:

  • Diphenyleneiodonium (inhibitor of NADPH oxidase) completely blocked TGF-beta-induced ROS, caspase-3 activation, and cell death.
  • Rotenone (inhibitor of mitochondrial complex I) partially attenuated ROS production, caspase activation, and cell death.
  • Inhibitors of cytochrome P450, cyclooxygenase, and xanthine oxidase showed no significant protective effects.
  • Evidence suggests both an inducible NADPH oxidase-like system and downregulation of antioxidant genes (e.g., MnSOD) contribute to ROS production.

Conclusions:

  • TGF-beta induces hepatocyte apoptosis primarily through ROS generated by an NADPH oxidase-like system.
  • Mitochondrial complex I contributes to, but is not the sole source of, TGF-beta-induced ROS.
  • TGF-beta-induced ROS production involves both extramitochondrial and intramitochondrial sources, alongside antioxidant gene downregulation.

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