Arsenite (NaAsO2) has been shown to produce vascular dysfunction in many studies. Arsenite-induced damage to vascular endothelial cells represents one of the possible mechanisms causing leakage of the vascular endothelial barrier. To explore arsenite-induced vascular endothelial damage, we used primary porcine aortic endothelial cells (PAECs) as an in vitro system to test the effects of arsenite on signal transduction pathways and apoptosis. Here we demonstrated that arsenite exposure induced apoptosis accompanied by the occurrence of apoptotic signals including degradation of poly(ADP-ribose) polymerase (PARP) and CPP32 (cleavage/activation) and DNA ladder formation. By using the luciferase reporter assay, we demonstrated that arsenite exposure differentially activated two redox-sensitive transcription factors, NF-kappaB and AP-1. Lower levels of arsenite exposure (25 muM NaAsO2, 24 h) induced co-activation of NF-kappaB and AP-1, accompanied by 9% total apoptosis. In contrast, higher levels of arsenite exposure (40 muM NaAsO2, 24 h) induced higher levels of AP-1 activation, accompanied by 45% total apoptosis. Blockade of NF-kappaB or JNK activity further enhanced arsenite-induced apoptosis. Upregulation of JNK activity showed no effect on arsenite-induced apoptosis. Based on these data, we propose that activation of redox-sensitive transcription factors, NF-kappaB and AP-1, plays a very important role in the protection of PAECs from arsenite-induced apoptosis. (C) 2003 Elsevier Inc. All rights reserved.
