Role of NADPH Oxidases in Disturbed Flow- and BMP4- Induced Inflammation and Atherosclerosis

Abstract

Atherosclerosis is an inflammatory disease, occurring preferentially in branched or curved arterial regions exposed to disturbed flow conditions including oscillatory shear stress (OS). In contrast, straight portions exposed to undisturbed laminar shear stress (LS) are relatively lesion free. The opposite effects of atheroprotective LS and proatherogenic OS are likely to be determined by differential expression of genes and proteins, including redox regulating factors. OS induces inflammation via mechanisms involving increased reactive oxygen species (ROS) production from the NADPH oxidases. Through a transcript profiling study and subsequent verification and functional studies, the authors discovered that OS induces inflammation by producing bone morphogenic protein 4 (BMP4) in endothelial cells. BMP4 stimulates expression and activity of NADPH oxidase requiring p47phox and Nox-1 in an autocrine-like manner. The NADPH oxidase activation by BMP4 then leads to ROS production, NF-kappaB activation, intercellular adhesion molecule 1 (ICAM-1) expression, and subsequent increased monocyte adhesivity of endothelial cells. It is proposed that endothelial NADPH oxidases play a critical role in disturbed flow- and BMP4-dependent inflammation, which is the critical early atherogenic response occurring in atheroprone areas. This emerging field of shear stress, BMP4, NADPH oxidases, inflammation, and atherosclerosis is reviewed.