Blockade of Oxidized LDL-Triggered Endothelial Apoptosis by Quercetin and Rutin through Differential Signaling Pathways Involving JAK2

Abstract

Oxidized LDL is highly atherogenic, as it stimulates foam cell formation and promotes inflammatory and thrombotic processes. The present study elucidated whether the antioxidants quercetin and its rutinoside rutin exert antiapoptosis in endothelial cells exposed to Cu(2+)-oxidized LDL. Quercetin and rutin inhibited the oxidized LDL-induced endothelial toxicity at nontoxic doses of </=25 muM with an inhibition of intracellular oxidant accumulation. These effects accompanied disappearance of apoptotic bodies and suppression of caspase-3 activation. Additionally, condensed nuclei vanished in oxidized LDL-exposed cells treated with quercetin and rutin. This study further explored whether such effects were achieved by redox manipulation via JAK2-STAT3-responsive death/survival signaling pathways involving multiple MAPK. Unlike quercetin, rutin blocked the activation of oxidized LDL-induced JNK and p38 MAPK as well as the upstream ASK1 phosphorylation. Quercetin dose-dependently attenuated the JAK2 phosphorylation evoked by oxidized LDL, whereas rutin abolished the JAK signaling accompanying nuclear transactivation of STAT3 and enhanced the JAK activity-inhibiting SOCS3 expression. Conversely, oxidized LDL-induced IL-6 release was minimal for the JAK2 activation, although this effect was counteracted by quercetin and rutin. These results suggest that quercetin and rutin inhibit Cu(2+)-oxidized LDL-induced endothelial apoptosis through modulating JAK2-STAT3 pathways and that rutin may modulate a signaling crosstalk between JAK2 and MAPK.