Abstract 15400: Stress Provokes Insulin Resistance and Impairs Endothelial NO Production in Mice Probably Through Activation of Endoplasmic Reticulum Stress and Inflammation Pathways by Corticotropin-releasing Hormone
Introduction: Previous studies suggested that psychological stress may provoke insulin resistance, although its mechanism is obscure. Corticotropin-releasing hormone (CRH) plays as a key regulator of hypothalamus under stress, however its role in the vascular cells and insulin signaling is not known well.
Hypothesis: Stress may provoke insulin resistance thus contributing to endothelial dysfunction probably by the role of CRH in insulin signaling pathway.
Methods and Results: Male C57BL/6 mice (8wk-old) were subject to immobilization stress (IS: 2 hr/d) and electric stimuli (ES: 12 times of 2 mA for 0.5 sec/d) for 2-4 wk. Control group comprised of mice without stress (n≥7 for each). Glucose tolerance test (i.p.) showed that stress (IS+ES) for 2 wk induced impaired glucose tolerance compared with control group. Stress (IS+ES) for 4 wk induced greater HOMA-IR than control group (2.5±0.6 vs. 0.8±0.3 mmol/LxμIU/mL, p<0.05). Total released NO in the aorta responding to acetylcholine (10-5M), measured by electrochemical microsensor, was significantly decreased in the stress (IS+ES,4 wk) group compared with control group (219.7±39.6 vs. 459.7±15.3 nM·sec, p<0.05). Western blot analysis of the liver showed that expression of phosphorylated ERK was greater in the IS+ES group compared with control group. In vitro cell adhesion assay showed that CRH (100 nM) induced a 4 folds increase (p<0.05) in U937 monocytes adhered to cultured HUVECs. CRH significantly enhanced mRNA expression of MCP-1 (2 folds, p<0.05) and increased nuclear translocation of NF-kB p65 subunit in cultured U937 monocytes. CRH induced an increase in Bip expression and enhanced phosphorylation of PERK, IRE1α, and eIF2α in cultured U937 monocytes, suggesting that CRH stimulates endoplasmic reticulum (ER) stress pathway. In cultured HUVECs, CRH induced IRS-1 serine phosphorylation thereby negatively regulating insulin signaling, and also inhibited insulin (2nM) stimulated eNOS phosphorylation at serine 1177.
Conclusions: These data suggest that stress can provoke insulin resistance along with impaired endothelial NO production probably through activation of CRH-mediated inflammation and ER stress pathways.
Author Disclosures: I. Chung: None. H. Kim: None. S. Yeon: None. I. Kim: None. Y. Lee: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.