Abstract 340: Psychological Stress Impairs Both Endothelial Function and Insulin Sensitivity via Activation of Inflammation and ER Stress Pathways Mediated by Corticotropin-Releasing Hormone
Background: Psychological stress may contribute to atherogenesis, although the underlying mechanism is poorly understood yet. We studied the role of corticotropin-releasing hormone (CRH) in the pathogenesis of stress-induced endothelial dysfunction and insulin resistance with specific focus on inflammation and ER stress pathways.
Methods and Results: Immobilization stress (IS) was applied (2 hr/d) for 14 d to male 8-wk OLETF rats, whereas control groups comprised of rats without IS (n≥7 for each). 14d-IS decreased acetylcholine (Ach)-induced NO production, measured by direct NO electrochemical microsensor, from the aorta along with decreased expression of eNOS mRNA compared with control group. 14d-IS did not significantly change plasma glucose, but increased plasma insulin (342.5±6.3 vs. 496.0±51.6 pg/ml, p<0.05) and HOMA-IR (3.1±0.2 vs.4.7±0.5 mmol/LxμIU/mL, p<0.05) compared with control group. IS increased phosphorylation of both IRS1 serine and ERK, and increased expression of ER stress marker BiP. IS also increased translocation of NF-kB subunit p65 into nucleal fraction, and increased mRNA expression of both TNF-α and MCP-1 in the liver. Real-time RT-qPCR study showed that 1d IS increased expression of CRH mRNA and urocortin 2 mRNA in the hypothalamus by 2.5 folds and expression of CRH receptor type 2 mRNA in the aorta by 7.8 folds compared with control group. In cultured monocyte U937 cells, CRH induced translocation of NF-kB subunit p65 into nuclear fraction, and increased expression of BiP, phosphorylated inositol requiring enzyme 1, and MCP-1 mRNA. In cultured HUVECs, CRH pretreatment inhibited insulin-stimulated eNOS phosphorylation at Ser1177.
Conclusions: Psychological stress impairs both endothelial function and insulin sensitivity probably via activation of NF-kB-mediated inflammation and ER stress pathways by CRH.
Author Disclosures: I. Chung: None. H. Kim: None. Y. Lee: None.
- © 2014 by American Heart Association, Inc.