Abstract 188: Immobilization Stress Exacerbates Insulin Resistance and Endothelial Dysfunction via Inhibition of Insulin-Stimulated eNOS Activation and via Enhancement of NF-kB Activation by Corticotropin-Releasing Hormone
Objectives Psychological stress may contribute to the development of atherosclerosis and insulin resistance. However, its mechanism is poorly understood. We studied if stress induces insulin resistance and endothelial dysfunction, and assessed the role of stress-associated corticotropin-releasing hormone (CRH) in inflammation and insulin signaling pathways.
Methods and Results Immobilization stress (IS) was applied (2 hr/d) for 14 d to male 8-wk (YI2O: before DM phenotype) and 21-wk (EI2O: DM phenotype) OLETF rats, whereas control groups comprised of rats without IS with same age (YCO and ECO, respectively; n=7~10 for each group). Systolic blood pressure was significantly increased after 14d-IS in YI2O and EI2O, whereas it was not changed in control groups. Acetylcholine-induced, but not nitroprusside-induced, vasorelaxation, measured in superior mesenteric artery, was significantly decreased by 14d IS compared with each control groups, suggesting that IS induced endothelial dysfunction. 14d-IS increased plasma insulin (342.5±6.3 vs 496±51.6 pg/ml) and HOMA-IR (3.1±0.2 vs 4.7±0.5 mmol/LxμIU/mL) in 8-wk OLETF rats (control vs stress, all p<0.05). Western blot analysis using thoracic aorta showed 14d-IS increased expression of Rho-associated kinase-1 and p22phox subunit of NAD(P)H oxidase compared with control groups. eNOS phosphorylation at Ser1177was increased by treatment with insulin (2nM) in cultured HUVEC cells, but this was blocked by pretreatment with CRH (100 nM). On the contrary, an increase in ERK phosphorylation by insulin treatment was further enhanced by CRH pretreatment in HUVEC cells. CRH also induced translocation of NF-kB subunit p65 into nuclear fraction in monocyte cell line U937 cells.
Conclusions Immobilization stress exacerbates insulin resistance and endothelial dysfunction in a prediabetic animal model at least partly via inhibition of insulin-mediated eNOS activation and via enhancement of inflammation through ERK pathway and NF-kB activation by CRH.
- © 2013 by American Heart Association, Inc.