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Interactions between cell death induced by statins and 7-ketocholesterol in rabbit aorta smooth muscle cells

W Martinet1, D M Schrijvers, J-P Timmermans

  • 1Division of Pharmacology, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium.

British Journal of Pharmacology
|May 13, 2008
PubMed
Abstract

Insights

7-Ketocholesterol induces smooth muscle cell (SMC) death via autophagy, while statins induce apoptosis. Their combined effects on cell death are not additive, suggesting differing mechanisms in atherosclerotic settings.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • 7-Ketocholesterol, an oxysterol found in atherosclerotic lesions, is known to cause smooth muscle cell (SMC) death.
  • Statins are cardioprotective but can induce SMC apoptosis, raising questions about their combined effects with 7-ketocholesterol.

Purpose of the Study:

  • To investigate the additive effects of statins and 7-ketocholesterol on SMC death.
  • To elucidate the distinct mechanisms of cell death induced by 7-ketocholesterol and statins.

Main Methods:

  • Cultured rabbit aorta SMCs were treated with 7-ketocholesterol and various statins (fluvastatin, simvastatin, pravastatin).
  • Cell viability was assessed using neutral red uptake.
  • Caspase activation and microtubule-associated protein 1 light chain 3 (LC3) processing (an autophagy marker) were measured.

Main Results:

  • 7-Ketocholesterol induced SMC death primarily through autophagy (LC3 processing).
  • Lipophilic statins (fluvastatin, simvastatin) induced SMC apoptosis (caspase activation) without LC3 processing.
  • At high concentrations, 7-ketocholesterol and statins showed additive cell death, but at lower statin concentrations, cell death was not additive, potentially due to autophagy interfering with caspase activation.

Conclusions:

  • 7-Ketocholesterol and lipophilic statins induce SMC death via distinct pathways: autophagy and apoptosis, respectively.
  • The non-additive cell death at lower statin concentrations suggests complex interactions between these pathways.
  • Drug effects observed in normal SMCs may not accurately predict outcomes in the context of atherosclerosis.

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