Activation of the Unfolded Protein Response in Vascular Endothelial Cells of Nondiabetic Obese Adults
Year: 2013
Type: article
Study design: Observational Study
Abstract: CONTEXT: Activation of the unfolded protein response (UPR) is emerging as an important molecular signature of cardiometabolic diseases associated with obesity. However, despite the well-established role of the vascular endothelium in obesity-related cardiometabolic dysfunction, it is unclear whether the UPR is activated in endothelial cells of obese adults. OBJECTIVE: The objective of the study was to determine whether markers of UPR activation are increased in endothelial cells (ECs) of nondiabetic obese adults with impaired endothelial function. DESIGN, SETTING, AND PARTICIPANTS: Endothelial cells were obtained from antecubital veins of the nondiabetic obese adults [body mass index (BMI) ≥ 30 kg/m(2), n = 12] with impaired endothelial function and from their nonobese peers (BMI < 30 kg/m(2), n = 14). MAIN OUTCOME VARIABLES: UPR activation via expression (quantitative immunofluorescence) of the proximal UPR sensors, inositol-requiring endoplasmic reticulum (ER)-to-nucleus signaling protein 1 (IRE1), RNA-dependent protein kinase-like ER eukaryotic initiation factor-2α kinase (PERK), and activating transcription factor 6 (ATF6), were the main outcome variables. RESULTS: IRE1 expression was greater in obese vs nonobese individuals (0.84 ± 0.09 vs 0.47 ± 0.02 IRE1 intensity/human umbilical vein EC (HUVEC) intensity (n = 10/8, P < .01). Obese individuals also had greater EC activation of UPR stress sensors PERK and ATF6, indicated by increased expression of phosphorylated PERK [p-PERK; 0.49 ± 0.05 vs 0.36 ± 0.03, p-PERK (threonine 981) intensity/HUVEC intensity, n = 10 men, 13 women, P < .05] and nuclear localization of ATF6 (0.38 ± 0.05 vs 0.23 ± 0.02, nuclear ATF6 intensity/HUVEC intensity, n = 5 men, 9 women, P < .01), respectively. Stepwise linear regression analysis revealed that indices of body fat (BMI and waist circumference) were the strongest independent predictors of all 3 UPR mediators, explaining between 18% and 59% of the variance in endothelial cell expression of IRE1, p-PERK, and nuclear ATF6 localization. CONCLUSION: These results provide novel evidence for UPR activation in the endothelial cells of nondiabetic obese adults with vascular endothelial dysfunction.
DOI: 10.1210/jc.2013-1841
Authors: Rachelle E. Kaplon, Eric Chung, Lauren Reese, Kimberly Cox-York, Douglas R. Seals, Christopher L. Gentile
Institutions: University of Colorado Boulder, Colorado State University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: G1125726563, G1625418467, Colorado Clinical and Translational Science Institute (UL1), G215709867, G360827231, G5193985868, Human Aging, Exercise & FMD: Translational Physiology, Nitrite Supplementation for Improving Physiological Function in Older Adults, G7187468479, G8164746466, Role of Endoplasmic Reticulum Stress in Obesity-Related Endothelial Dysfunction, Integrative Physiology of Aging Training Grant
OpenAlex ID: W2146063286