title: NADPH oxidase 4 mediates monocyte priming and accelerated chemotaxis induced by metabolic stress.
abstract: 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.
  
  
  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 H(2)O(2) formation, stimulated protein S-glutathionylation, and increased chemotaxis in response to MCP-1, platelet-derived growth factor B, and RANTES. Both H(2)O(2) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Laboratory Sciences, School of Health Professions, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Drive, MC 6246, San Antonio, TX 78229-3900, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ullevig
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhao
authors.forename: Chi Fung
authors.initials: CF
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Seok Kim
authors.forename: Debora
authors.initials: D
authors.lastname: Zamora
authors.forename: Reto
authors.initials: R
authors.lastname: Asmis
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D000199:Actins; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D020574:Proto-Oncogene Proteins c-sis; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse
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