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* Cardiovascular Research Center, Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and
Center for Cardiovascular Research, Albany Medical College, Albany, New York, USA
1Correspondence: Cardiovascular Research Center and Department of Anatomy and Cell Biology, Temple University School of Medicine, 3420 North Broad St., MRB826, Philadelphia, PA 19140, USA. E-mail: rizzov{at}temple.edu
ABSTRACT
Reactive oxygen species (ROS) generated during pathological events, such as inflammation and ischemia-reperfusion, activates both proapoptotic and antiapoptotic signaling programs in endothelial cells. Because cholesterol-rich, plasma membrane rafts serve as platforms for organizing and integrating signaling transduction processes, we asked whether these membrane regions play a mechanistic role in H2O2-induced responses. Bovine aortic endothelial cell cultures exposed to a 500-µM bolus of H2O2 showed progressive activation of caspase 3 and an increase in the number of TUNEL-positive cells. Pretreatment with either wortmannin or PD 098059 heightened these apoptotic responses, demonstrating that both PI3 kinase/Akt and ERK1/2 serve as signaling mediators to alleviate H2O2 cytotoxic effects. To investigate the role of lipid rafts in these signaling processes, endothelial cells were pretreated with methyl-ß-cyclodextrin (CD) or filipin to ablate raft structures. H2O2-induced phosphorylation of Akt and ERK 1/2 was attenuated, while caspase 3 and the number of TUNEL positive cells was enhanced in CD-pretreated cells exposed to H2O2. Reconstitution of raft domains restored H2O2-induced Akt and ERK1/2 phosphorylation, which was concomitant with reduction of caspase 3 activation and DNA fragmentation. Taken together, our findings suggest that plasma membrane compartments rich in cholesterol participate in signal transduction pathways activated by oxidative stress.—Yang, B., Oo, T. N., and Rizzo, V. Lipid rafts mediate H2O2 prosurvival effects in cultured endothelial cells.
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