Disturbed-Flow-Mediated Vascular Reactive Oxygen Species Induce Endothelial Dysfunction

Emerging evidence is revealing the different roles of steady laminar flow (s-flow) and disturbed flow (d-flow) in the regulation of the vascular endothelium. s-flow is atheroprotective while d-flow creates an atheroprone environment. Most recently, we found unique atheroprone signals, which involve protein kinase C (PKC)zeta activation, elicited by d-flow. We and others have defined a novel role for PKC zeta as a shared mediator for tumor necrosis factor alpha (TNF alpha) and d-flow, which cause pro-inflammatory and pro-apoptotic events in endothelial cells (ECs) in the atheroprone environment. Under such conditions, ONOO- formation is increased in a d-flow-mediated PKC zeta-dependent manner. Here, we propose a new signaling pathway involving d-flow-induced EC inflammation via PKC interaction-mediated downregulation of KLF2/eNOS stability, which leads to PKC zeta-mediated p53-SUMOylation and EC apoptosis. In addition, we highlight several mechanisms contributing to endothelial dysfunction, focusing on the relations between flow patterns and activation of reactive oxygen species generating enzymes. (Circ J 2011; 75:2722-2730)