Abstract 17334: Stress Provokes Endothelial Dysfunction and Insulin Resistance Partly Through Activation of NF-kB and Inhibition of Insulin Signaling Pathway to NO Production by Corticotropin-releasing Hormone
Background: Psychological stress probably contributes to development of atherosclerosis and insulin resistance. However, its underlying mechanism is poorly understood. We studied if stress induces insulin resistance and endothelial dysfunction, and assessed the role of corticotropin-releasing hormone (CRH), known to play a key role in stress physiology, in insulin signaling and inflammation.
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 OLETF rats without IS with the same age (YCO and ECO, respectively; n=7~10 for each). 14d-IS impaired acetylcholine (Ach)-induced, but not nitroprusside-induced, vasorelaxation in superior mesenteric arteries measured by a mechanotransducer in YI2O group and EI2O group, compared with each control group. In addition, the amount of Ach-stimulated NO release, measured by direct NO electrochemical microsensor, from the aorta was also decreased along with a decrease in eNOS mRNA by 62%, measured by RT-qPCR, in YI2O group vs. YCO group (all, p<0.05). 14d-IS did not change plasma glucose (126.0±7.0 vs. 132.8±2.0 mg/dL, p=NS), but increased 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) in YI2O group vs. YCO group. Expression of hepatic TNF-α mRNA was increased by 2.8 fold in YI2O group vs. YCO group (p<0.05). Expression of Rho-associated kinase-1 and p22phox subunit of NAD(P)H oxidase in aorta, analyzed by Western blot, was significantly increased in EI2O vs. ECO group. CRH induced translocation of NF-kB subunit p65 into nuclear fraction in cultured monocyte U937 cells. Insulin (2nM) stimulated eNOS phosphorylation at Ser1177 in cultured HUVECs, which was inhibited by pretreatment with CRH (100 nM).
Conclusions: Stress provokes endothelial dysfunction along with inflammation, insulin resistance, and decreased endothelial NO production. CRH at least partly play a significant role in this constellation of stress-induced pathophysiology by promoting inflammation via activation of NF-kB and inhibiting insulin signaling pathway to NO production through eNOS.
- © 2013 by American Heart Association, Inc.