Resistin-Induced Endoplasmic Reticulum Stress Contributes to the Impairment of Insulin Signaling in Endothelium.

Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of obesity, insulin resistance and cardiovascular diseases (CVDs). Impairment of insulin vascular action may represent a mechanism linking insulin resistance and CVDs. The present study tested the hypothesis that adipocyte-derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress. Human umbilical vein endothelial cells (HUVC) were incubated with tunicamycin (an inducer of ER stress, 1-20 μg/mL) or resistin (10-100 ng/mL) for 1 h. Either tunicamycin or resistin increased GRP78 (an ER stress marker) expression associated with the impairment of insulin-stimulated Akt/eNOS phosphorylation, which were prevented by TUDCA (an ER stress suppressor). Resistin increased reactive oxygen species (ROS) production, antioxidant treatment inhibited resistin-induced GRP78 expression and impairment of insulin Akt/eNOS signaling, suggesting that ROS may involve resistin-induced ER stress. Resistin also increased JNK phosphorylation, which was prevented by TUDCA. JNK inhibitor SP600125 relieved the resistin inhibitory effects on endothelial insulin Akt/eNOS signaling. In experiments, the incubation of aortic rings with resistin impaired insulin- but not acetylcholine-induced vasodilation, which was restored by TUDCA. LNAME (a NOS inhibitor) abolished insulin-induced vasorelaxation in the control or the resistin-treated aortic rings. In addition, resistin increased the mRNA expressions of proinflammatory cytokines tumor nuclear factor (TNF)α and interleukin (IL)-1β, which were also prevented by TUDCA. Our results support the ideal that ER stress may play an important role for resistin impairment of vascular insulin signaling and insulin action. The mitigation of ER stress may represent a new strategy for prevention and treatment of CVDs in obesity and insulin resistant-related diseases.