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Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice

S Shalini1, L Dorstyn, C Wilson

  • 1Centre for Cancer Biology, SA Pathology, Adelaide, Australia.

Cell Death and Differentiation
|February 21, 2012
PubMed

Insights

Caspase-2 deficiency exacerbates oxidative stress and aging phenotypes in mice. This suggests caspase-2 (casp2) plays a crucial role in cellular stress response and longevity.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Gerontology

Background:

  • Caspase-2 (casp2) is known to regulate apoptosis, cell cycle, tumor suppression, and aging.
  • Its precise role in the aging process and stress response remains incompletely understood.

Purpose of the Study:

  • To investigate the role of caspase-2 in the stress response pathway and its contribution to aging.
  • To elucidate the molecular mechanisms underlying caspase-2's influence on oxidative stress.

Main Methods:

  • Utilized caspase-2 knockout (casp2(-/-)) mice and wild-type littermates for comparative analysis.
  • Assessed cellular markers of oxidative stress, including oxidized proteins, lipid peroxides, and DNA damage.
  • Measured reactive oxygen species (ROS) generation in murine embryonic fibroblasts.
  • Quantified the activities of antioxidant enzymes like glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD).
  • Analyzed the expression levels of key proteins such as FoxO1, FoxO3a, and p21.

Main Results:

  • Old casp2(-/-) mice exhibited increased markers of oxidative stress and DNA damage compared to wild-type controls.
  • Murine embryonic fibroblasts from casp2(-/-) mice showed heightened ROS production upon pro-oxidant challenge.
  • Reduced activities of GSH-Px and SOD were observed in aged casp2(-/-) mice.
  • Expression of FoxO1 and FoxO3a was significantly decreased, while p21 levels and senescent hepatocyte counts were elevated in old casp2(-/-) mice.
  • Caspase-2 deficient mice on an ethanol-based diet failed to upregulate GSH-Px and SOD activities.

Conclusions:

  • Caspase-2 plays a significant role in regulating the oxidative stress response in vivo.
  • The anti-aging effects of caspase-2 may be partly mediated through its involvement in the stress response pathway.
  • Caspase-2 likely influences oxidative stress regulation via the FoxO transcription factors.

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