NADPH Oxidase 4 Mediates Monocyte Priming and Accelerated Chemotaxis Induced by Metabolic Stress

作者：Ullevig Sarah; Zhao Qingwei; Lee Chi Fung; Kim Hong Seok; Zamora Debora; Asmis Reto^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2012, 32(2): 415-U599.

DOI：10.1161/ATVBAHA.111.238899

• macrophages
• chemotaxis
• glutaredoxin
• Nox4

Objective-Metabolic disorders increase monocyte chemoattractant protein-1 (MCP-1)-induced monocyte chemotaxis in mice. The goal of this study was to determine the molecular mechanisms responsible for the enhanced responsiveness of monocytes to chemoattractants induced by metabolic stress. %26lt;br%26gt;Methods and Results-Chronic exposure of monocytes to diabetic conditions induced by human LDL plus high D-glucose concentrations (LDL + HG) promoted NADPH Oxidase 4 (Nox4) expression, increased intracellular H2O2 formation, stimulated protein S-glutathionylation, and increased chemotaxis in response to MCP-1, platelet-derived growth factor B, and RANTES. Both H2O2 added exogenously and overexpression of Nox4 mimicked LDL + HG-induced monocyte priming, whereas Nox4 knockdown protected monocytes against metabolic stress-induced priming and accelerated chemotaxis. Exposure of monocytes to LDL + HG promoted the S-glutathionylation of actin, decreased the F-actin/G-actin ratio, and increased actin remodeling in response to MCP-1. Preventing LDL + HG-induced protein S-glutathionylation by overexpressing glutaredoxin 1 prevented monocyte priming and normalized monocyte chemotaxis in response to MCP-1. Induction of hypercholesterolemia and hyperglycemia in C57BL/6 mice promoted Nox4 expression and protein S-glutathionylation in macrophages, and increased macrophage recruitment into MCP-1-loaded Matrigel plugs implanted subcutaneous in these mice. %26lt;br%26gt;Conclusion-By increasing actin-S-glutathionylation and remodeling, metabolic stress primes monocytes for chemoattractant-induced transmigration and recruitment to sites of vascular injury. This Nox4-dependent process provides a novel mechanism through which metabolic disorders promote atherogenesis. (Arterioscler Thromb Vasc Biol. 2012; 32: 415-426.)

• 出版日期2012-2