title: Increased monocyte-derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress.
abstract: What is the central question of this study? Patients with type 2 diabetes exhibit increased oxidative stress in peripheral blood mononuclear cells, including monocytes; however, the mechanisms remain unknown. What is the main finding and its importance? The main finding of this study is that factors contained within the plasma of patients with type 2 diabetes can contribute to increased oxidative stress in monocytes, making them more adherent to endothelial cells. We show that these effects are largely mediated by the interaction between endoplasmic reticulum stress and NADPH oxidase activity. Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum (ER) stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n = 8) and compared the values with age-matched healthy control subjects (n = 8). The T2D patients exhibited greater basal intracellular ROS (mean ± SD, +3.4 ± 1.4-fold; P < 0.05) compared with control subjects. Next, the increase in ROS in PBMCs isolated from T2D patients was partly recapitulated in cultured human monocytes (THP-1 cells) exposed to plasma from T2D patients for 36 h (+1.3 ± 0.08-fold versus plasma from control subjects; P < 0.05). In addition, we found that increased ROS formation in THP-1 cells treated with T2D plasma was NADPH oxidase derived and led to increased endothelial cell adhesion (+1.8 ± 0.5-fold; P < 0.05) and lipid uptake (+1.3 ± 0.3-fold; P < 0.05). Notably, we found that T2D plasma-induced monocyte ROS and downstream functional effects were abolished by treating cells with tauroursodeoxycholic acid, a chemical chaperone known to inhibit ER stress. Collectively, these data indicate that monocyte ROS production with T2D can be attributed, in part, to signals from the circulating environment. Furthermore, an interplay between ER stress and NADPH oxidase activity contributes to ROS production and may be a mechanism mediating endothelial cell adhesion and foam cell formation in T2D.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Restaino
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
authors.forename: Shekhar H
authors.initials: SH
authors.lastname: Deo
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Parrish
authors.affiliation: Department of Kinesiology, University of Texas-Arlington, Arlington, TX, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fadel
authors.affiliation: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.|Department of Child Health, University of Missouri, Columbia, MO, USA.
authors.forename: Jaume
authors.identifier: 0000-0002-7944-4936
authors.initials: J
authors.lastname: Padilla
mesh_terms: D016022:Case-Control Studies; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000074084:THP-1 Cells / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases
keywords: NADPH oxidase; PBMCs; endothelial cell adhesion; lipid uptake; oxidative stress