Submitted on August 1, 2005
Accepted on August 18, 2005
Apolipoprotein A-IV attenuates oxidant-induced apoptosis in mitotic competant, undifferentiated cells by modulating intracellular glutathione redox balance
Heather L Spaulding1, Fumito Saijo1, Richard H Turnage1, Jonathan S Alexander2, Tak Yee Aw2, and Theodore J Kalogeris3*
1 Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
2 Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
3 Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
* To whom correspondence should be addressed. E-mail: tkalog{at}lsuhsc.edu.
Oxidant-mediated modulation of intracellular redox state affects the apoptotic cascade by altering the balance between cellular signals for survival and suicide. Apolipoprotein A-IV (apo A-IV) is known to possess antioxidant-like activity. Here, we tested 1) whether apo A-IV could influence redox-dependent apoptosis, and if so, 2) whether such an effect could be mediated by modulation of intracellular redox balance. Mitotic competent, undifferentiated PC-12 cells were incubated with either tert-butyl hydroperoxide (TBH) or diamide with or without preincubation with human apo A-IV. Apo A-IV significantly decreased apoptosis produced by both TBH and diamide; washout of A-IV prior to incubation with TBH and diamide did not eliminate its protective effect. Apo A-I had no such protective effect; the A-IV effect was not blocked by DL-buthionine-[S,R]-sulfoximine, but was reversed by both dehydroisoandrosterone and transfection with an antisense oligodeoxynucleotide to glucose-6-phosphate dehydrogenase (G6PD). Apo A-IV abolished the transient, oxidant-induced rise in glutathione disulfide (GSSG) and cellular redox imbalance previously shown to initiate the apoptotic cascade. Apo A-IV had no effect on GSSG reductase activity, but stimulated G6PD activity 10-fold. These results suggest a novel role for apo A-IV in the regulation of intracellular glutathione redox balance and modulation of redox-dependent apoptosis via stimulation of G6PD activity.
