title: Evidence for a non-antioxidant, dose-dependent role of alpha -lipoic acid in caspase-3 and ERK2 activation in endothelial cells.
abstract: Endothelial cell apoptosis contributes to atherosclerosis and may be exacerbated by oxidative stress. Results from clinical trials using antioxidant supplementation are equivocal and could be enhanced by antioxidants with additional non-antioxidant properties such as alpha -lipoic acid and alpha -tocopherol. The aim of this study was to investigate the effects of these antioxidants on cytoprotective pathways and endothelial apoptosis. Endothelial cells were incubated with alpha -lipoic acid and alpha -tocopherol, alone or in combination, prior to incubation with H(2)O(2) or staurosporine. alpha -lipoic acid pre-treatment alone increased caspase-3 activity in a dose-dependent manner. Both H(2)O(2) and staurosporine increased DNA fragmentation and caspase-3 activity and pre-treatment of cells with alpha -lipoic acid and/or alpha -tocopherol failed to prevent stress-induced apoptosis. Neither antioxidant treatments nor apoptotic inducers alone altered expressions of Bcl-2, Bax, HSP70 or pERK1/2 or pJNK. alpha -lipoic decreased pERK2 in staurosporine-treated cells in a dose-dependent manner. These findings indicate that pre-incubation with alpha -lipoic acid and alpha -tocopherol, alone or in combination, does not protect against oxidative- or non-oxidative-induced apoptosis in endothelial cells. Moreover, we have demonstrated a non-antioxidant, dose-dependent role of alpha -lipoic acid in caspase-3 and ERK2 activation. These data provide an insight and indicate caution in the use of high doses of alpha -lipoic acid as an antioxidant.
authors.affiliation: School of Human Movement Studies, The University of Queensland, Brisbane, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Marsh
authors.forename: B K
authors.initials: BK
authors.lastname: Pat
authors.forename: G C
authors.initials: GC
authors.lastname: Gobe
authors.forename: J S
authors.initials: JS
authors.lastname: Coombes
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D008063:Thioctic Acid / Q000008:administration & dosage / Q000502:physiology*; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C088008:Tmbim6 protein, rat; D008063:Thioctic Acid; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D024502:alpha-Tocopherol; D019311:Staurosporine