Critical role of the NADPH oxidase subunit p47phox on vascular TLR expression and neointimal lesion formation in high-fat diet-induced obesity

Abstract

Reactive oxygen species (ROS) formation is associated with inflammation and vasculature dysfunction. We investigated the potential role of the NADPH oxidase on vascular Toll-like receptor (TLR) expression and carotid neointimal formation in high-fat (HF) diet-induced obesity (DIO) model. Using mice DIO and common carotid artery flow cessation-induced lesion formation models, we examined vascular TLR2 and TLR4 expression and neointimal formation in NADPH oxidase subunit p47 phox -deficient (p47 phox-/-) mice. Feeding C57BL/6J mice an HF diet for 22 weeks resulted in significant increases in p47 phox , TLR2 and TLR4 expression in vascular tissues compared with mice fed a low-fat (LF) diet. Minimal changes in TLR2 and TLR4 expression was detected in p47 phox-/-DIO mice. Furthermore, flow cessation-induced angiogenic and inflammatory response and neointimal formation were significantly attenuated in p47 phoxÀ/À DIO mice compared with wild-type DIO mice. In addition, exposure of endothelial cells to leptin led to ROS formation; this was accompanied by upregulation of TLR2, TLR4 expression and its downstream signaling. Leptin also increased endothelial cell migration and proliferation. Pharmacological inhibition of NADPH oxidase or genetic deletion of p47 phox significantly diminished these alterations. Obesity increases neointimal formation via a mechanism involving p47 phox -TLRs signaling, suggesting that the NADPH oxidase may represent a potential novel therapeutic target for the treatment of obesity-associated vascular inflammation and dysfunction.

Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy

“…This was also confirmed with knockout of the p47 phox subunit of NADPH oxidase (7). NADPH oxidase composed of p22 phox , p47 phox , and p67 phox plays a crucial role in the generation of ROS and hence serves a potential role in providing a host defense.…”

The Effects of Adiponectin and Leptin on Human Endothelial Cell Proliferation: A Live-Cell Study

“…Similarly, leptin at a low dose is unable to modify endothelial progenitor cell migration in response to a scratch wound [46], although at a high dose it is able to reduce the migration of these cells. However, the specific role of leptin on endothelial cell migration seems unclear because some studies have reported that this factor can act as a chemoattractive factor in endothelial cells [40,47]. …”

Obesity abrogates the concentration-dependent effect of leptin on endogenous cholesterol synthesis in human monocytes

“…Abbreviations: 25-HC, 25-hydroxycholesterol; HMG CoA reductase, 3-hydroxy-3-methylglutaryl CoA reductase; AUC, areas under curves; cPKC, conventional proteinkinase C; ERK, extracellular signal-regulated kinase; HBSS, Hanks balanced salt solution; HC, hypercholesterolemia; JAK/STAT, janus kinase/signal transducer and activator of transcription; MAPK, mitogen activated proteinkinase; OW monocytes, monocytes derived from overweight patients; NFB, nuclear factor B; PTX, pertussis toxin; PMA, phorbol 12-myristate 13-acetate; PI3K, phosphatidilinositol 3 kinase; SREBP2, sterol regulatory element-binding protein2; SCAP, SREBP cleavageactivating protein; SOCS, suppressor of cytokine signaling; WMN, wortmannin. Through these signal pathways leptin exerts many physiological and pathological effects on its target-cells, both by directly modifying protein function in the cytoplasm and through gene expression regulation in the nucleus (Dong et al 2006;Chen and Stinnett 2008). We found a concentration-dependent biphasic effect of leptin on cholesterol biosynthesis of control monocytes.…”