Abstract P341: Osteoprotegerin-induced ROS Production and Redox Signalling is Exacerbated in Hypertension and Involves Syndecan-1 and TRPM2 Activation

Osteoprotegerin (OPG) levels are increased in metabolic diseases, and are a biomarker of vascular dysfunction and cardiovascular risk. Mechanisms related to OPG-induced vascular dysfunction and its role in hypertension are not fully understood, but we previously demonstrated that OPG induces vascular dysfunction through ROS-dependent mechanisms. Here we assessed the molecular mechanisms whereby OPG regulates ROS and vascular function, with a focus on syndecan-1. VSMCs from normotensive (WKY) and hypertensive (SHRSP) rats were stimulated with OPG (50 ng/mL). ROS production was measured by lucigenin, amplex red and ELISA. In VSMCs from WKY rats, OPG increased ROS generation (158±15% vs veh, p2 O 2 (2 fold) and ONOO - (1.5 fold) levels in VSMCs (p2 O 2 further stimulates ROS levels and redox signalling through activation of TRPM2, a redox-sensitive Ca 2+ channel. TRPM2 inhibitors, 8-bromo-ADPR (8Br) and N-(p-amylcinnamoyl)anthranilic acid (ACA), did not block OPG-induced ROS generation in VSMCs from WKY rats. Syndecan-1 activation leads to FAK and c-Src activation, which are redox-sensitive signalling proteins. FAK, but not c-Src, activation (117±2%, p