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.

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

“…Oscillatory sheer stress results in several-fold induction of Nox1, Nox2 and Nox4 in vascular endothelium (with opposite effects of the anti-atherogenic laminar flow that occurs in straight portions of vessels) [80,81]. Oscillatory sheer stress is associated with induction of bone morphogenic protein 4 (BMP4) [82], which induces Nox1 and p47phox, resulting in an oxidative stress that leads to ICAM-1 expression and monocyte adhesion [81]. Nox1 expression increases ~3-fold following balloon injury and precedes restenosis and atherosclerosis [83].…”

Flow-dependent cellular mechanotransduction in atherosclerosis

“…Modified LDLs are also potentially immunogenic and might stimulate adaptive immunity, leading to the generation of autoantibodies and to activated T cells that contribute to inflammation (Ketelhuth and Hansson, 2011). Disturbed shear stimulates reactive oxygen species (ROS) production by ECs in part through activation of the NADPH oxidase (reviewed by Jo et al, 2006), which oxidizes the retained LDL. Disturbed flow also reduces the expression of Mn-superoxide dismutase, which contributes to elevated ROS (Ai et al, 2008).…”

Discovery of novel mechanosensitive genes in vivo using mouse carotid artery endothelium exposed to disturbed flow

“…[5][6][7][8] To define molecular mechanisms responsible for these changes, investigators have carried out DNA microarray studies using endothelial cells [9][10][11][12][13][14][15][16][17] and have subsequently identified numerous shear-sensitive genes, such as kruppel-like factor 2 and 4 (Klf2, Klf4), endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), bone morphogenic protein 4 (BMP-4), cathepsins, and angiopoietin-2 (Angpt2). 11,14,[18][19][20][21][22][23][24][25][26][27][28][29] Functional studies based on these shear-sensitive genes and their protein products have revealed the critical roles that they play in regulation of inflammation, thrombosis, vascular remodeling, angiogenesis, and arteriogenesis.…”