Abstract
Background: 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.Methods and Results: 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 ex vivo 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.Conclusion: 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.
Highlights
The growing obesity epidemic and its associated metabolic dysfunction have made adipose tissue an important target of therapeutic interventions
To examine whether Endoplasmic reticulum (ER) stress impairs insulin signaling in endothelium, HUVECs were incubated with vehicle (0.02% DMSO) and tunicamycin at the dose of 1, 5, 10, and 20 μg/mL dissolved in 0.02% DMSO solution for 1 h, tunicamycin dose-dependently increased the protein expression of glucose regulated protein 78 (GRP78), an ER stress marker (Figure 1A)
These results suggest that tunicamycin-induced ER stress can inhibit insulin-stimulated Akt and endothelial nitric oxide synthase (eNOS) pathway in endothelium
Summary
The growing obesity epidemic and its associated metabolic dysfunction have made adipose tissue an important target of therapeutic interventions. Adipose tissue is an energy storage organ, and an active endocrine organ that secretes many unique proteins known as adipokines such as resistin, adiponectin, leptin, tumor necrosis factor (TNF)α (Sidossis and Kajimura, 2015; Kumari et al, 2018). Excessive expansion of adipose tissue may dysregulate the expressions (or secretions) of adipokines, leading to various metabolic abnormalities such as hyperlipidemia and hyperglycemia, which in turn induce insulin resistance and cardiovascular diseases (CVDs) (Lau et al, 2005; Bartelt and Heeren, 2014). The changes in adipose tissue mass and metabolism may be a molecular link among insulin resistance, CVDs and visceral obesity (Verma et al, 2003; Fisman and Tenenbaum, 2014). The present study tested the hypothesis that adipocyte-derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress
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