NADPH oxidase 4 mediates monocyte priming and accelerated chemotaxis induced by metabolic stress.
NADPH oxidase 4 mediates monocyte priming and accelerated chemotaxis induced by metabolic stress.
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DOI：
10.1161/atvbaha.111.238899
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Asmis R
中科院分区：
文献类型：
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作者：
Ullevig S;Zhao Q;Lee CF;Seok Kim H;Zamora D;Asmis R
代谢紊乱增加小鼠MCP-1诱导的单核细胞趋化性。本研究的目的是确定负责增强单核细胞对代谢应激诱导的化学引诱物的反应性的分子机制。慢性暴露的单核细胞的糖尿病条件下诱导的人低密度脂蛋白加高D-葡萄糖浓度（LDL+HG）促进Nox 4的表达，增加细胞内H2 O2的形成，刺激蛋白S-谷胱甘肽化，并增加趋化反应MCP-1，PDGF-B和RANTES。外源性添加H2 O2和过表达Nox 4均模拟LDL+ HG诱导的单核细胞启动，而Nox 4敲低则保护单核细胞免受代谢应激诱导的启动和加速趋化。暴露于LDL+HG的单核细胞促进肌动蛋白的S-谷胱甘肽化，降低F-actin/G-actin比值，并增加肌动蛋白对MCP-1的重塑。通过过量表达谷氧还蛋白1（Grx 1）来阻止LDL+ HG诱导的蛋白S-谷胱甘肽化，可阻止单核细胞启动和正常化单核细胞对MCP-1的趋化反应。在C57 BL/6小鼠中诱导高胆固醇血症和高血糖促进了巨噬细胞中的Nox 4表达和蛋白-S-谷胱甘肽化，并增加了巨噬细胞向皮下植入的MCP-1负载的基质胶塞中的募集。通过增加肌动蛋白-S-谷胱甘肽化和重塑，代谢应激引发单核细胞进行化学引诱剂诱导的迁移和招募到血管损伤部位。这种Nox 4依赖性过程提供了一种新的机制，通过这种机制，代谢紊乱促进动脉粥样硬化形成。
Metabolic disorders increase 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. Chronic exposure of monocytes to diabetic conditions induced by human low-density lipoproteins plus high D-glucose concentrations (LDL+HG) promoted Nox4 expression, increased intracellular H2O2 formation, stimulated protein S-glutathionylation, and increased chemotaxis in response to MCP-1, PDGF-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 (Grx1) 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. 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.