EGF receptor-dependent JNK activation is involved in arsenite-induced p21 upregulation and endothelial apoptosis

Nuntharatanapong, Nopparat, Kai Chen, Palarp Sinhaseni, and John F. Keaney, Jr. EGF receptor-dependent JNK activation is involved in arsenite-induced p21 upregulation and endothelial apoptosis. Am J Physiol Heart Circ Physiol 289: H99–H107, 2005. First published February 25, 2005; doi:10.1152/ajpheart.00901.2004.—Arsenic exposure is associated with an increased risk of atherosclerosis and vascular diseases. Although endothelial cells have long been considered to be the primary targets of arsenic toxicity, the underlying molecular mechanism remains largely unknown. In this study, we sought to explore the signaling pathway triggered by sodium arsenite and its implication for endothelial phenotype. We found that sodium arsenite produced timeand dose-dependent decreases in human umbilical vein endothelial cell viability. This effect correlated with the induction of p21 (up to 10-fold), a regulatory protein of cell cycle and apoptosis. We also found that arsenite-stimulated EGF (ErbB1) and ErbB2 receptor transactivation, manifest as receptor tyrosine phosphorylation, appeared to be a proximal signaling event leading to p21 induction, because both pharmacological inhibitors and knockdown of receptors by RNA interference blocked arsenite-induced p21 upregulation. Arsenite-induced activation of JNK and p38 MAPK was distinct, with only JNK as a downstream target of the EGF receptor. Moreover, inhibition of JNK with SP-600125 or dominant negative MKK7 inhibited only p21 induction, whereas the p38 MAPK inhibitor SB-203580 or dominant negative MKK4 inhibited both p21 and p53 induction. Functionally, inhibition of p21 induction prevented endothelial apoptosis due to arsenite treatment. Insofar as endothelial dysfunction promotes vascular disease, these data provide a mechanism for the increased incidence of cardiovascular disease due to arsenite exposure.