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Inhibition of inflammatory endothelial responses by a pathway involving caspase activation and p65 cleavage

J Neuzil1, A Schröder, P von Hundelshausen

  • 1Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Munich, Germany. jneuzil@klp.med.uni-muenchen.de

Biochemistry
|April 11, 2001
PubMed

Insights

Alpha-tocopheryl succinate (alpha-TOS) induces endothelial cell apoptosis by activating caspases, which suppress NF-kappa B (Nuclear Factor kappa B) activation. This links pro-apoptotic and anti-inflammatory pathways by inhibiting monocyte recruitment.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Endothelial cell (EC) apoptosis involves suppressing survival pathways, with NF-kappa B (Nuclear Factor kappa B) activation playing a role.
  • Alpha-tocopheryl succinate (alpha-TOS) is a compound investigated for its effects on cell survival and apoptosis.

Purpose of the Study:

  • To investigate the role of alpha-tocopheryl succinate (alpha-TOS) in inducing endothelial cell (EC) apoptosis.
  • To elucidate the molecular mechanisms linking EC apoptosis to NF-kappa B (Nuclear Factor kappa B) signaling and inflammatory responses.

Main Methods:

  • Utilized alpha-tocopheryl succinate (alpha-TOS) to induce apoptosis and trigger apoptosome formation and caspase activation in ECs.
  • Assessed changes in Bcl-2 levels, proliferation index, and TUNEL-positive apoptosis.
  • Employed the pan-caspase inhibitor z-VAD.fmk and stable transfection with caspase-resistant p65 mutants to study NF-kappa B (Nuclear Factor kappa B) pathway involvement.

Main Results:

  • Alpha-TOS (alpha-tocopheryl succinate) induced EC apoptosis, reduced Bcl-2 levels, and was associated with a high proliferation index.
  • Caspase activation, triggered by alpha-TOS, led to p65 cleavage, inhibited NF-kappa B (Nuclear Factor kappa B) nuclear translocation, and suppressed TNF alpha-induced inflammatory gene expression (VCAM-1) and monocytic cell adhesion.
  • These effects were linked to p65 cleavage, as a caspase-noncleavable p65 mutant preserved NF-kappa B (Nuclear Factor kappa B)-dependent transactivation.

Conclusions:

  • Caspase activation in ECs, induced by alpha-TOS, inhibits NF-kappa B (Nuclear Factor kappa B)-dependent inflammatory activation and monocyte recruitment.
  • Demonstrated a direct link between alpha-TOS-induced apoptosis and the suppression of inflammatory pathways via caspase-mediated p65 cleavage.
  • Provided evidence for a relationship between pro-apoptotic and anti-inflammatory signaling in endothelial cells.

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