Resistin-Induced Endoplasmic Reticulum Stress Contributes to the Impairment of Insulin Signaling in Endothelium.
Resistin-Induced Endoplasmic Reticulum Stress Contributes to the Impairment of Insulin Signaling in Endothelium.
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抵抗素诱导的内质网应激导致内皮细胞胰岛素信号传导受损
DOI：
10.3389/fphar.2018.01226
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发表时间：
2018
影响因子：
5.6
通讯作者：
Zhou MS
中科院分区：
文献类型：
--
作者：
Luo J;Huang L;Wang A;Liu Y;Cai R;Li W;Zhou MS
背景资料：内质网应激在肥胖、胰岛素抵抗和心血管疾病的发病机制中起重要作用。胰岛素血管作用受损可能是胰岛素抵抗和心血管疾病的联系机制。本研究验证了这一假设，即脂肪细胞源性的β-胡萝卜素抑制胰岛素刺激的内皮细胞NO的生产，通过诱导内质网应激。方法和结果：将人脐静脉内皮细胞（HUVC）与衣霉素（ER应激诱导剂，1 - 20 μ g/mL）或阿糖胞苷（10 - 100 ng/mL）孵育1 h。衣霉素或Glycin增加GRP78（一种ER应激标志物）表达，这与胰岛素刺激的Akt/eNOS磷酸化受损有关，TUDCA（一种ER应激抑制剂）可阻止这一点。抵抗素增加活性氧（ROS）的产生，抗氧化剂处理抑制了抵抗素诱导的GRP78表达和胰岛素Akt/eNOS信号通路的损伤，提示ROS可能参与了抵抗素诱导的内质网应激。抵抗素也增加JNK磷酸化，这是由TUDCA阻止。JNK抑制剂SP600125可减轻JNK对内皮胰岛素Akt/eNOS信号通路的抑制作用。在离体实验中，主动脉环的孵育与Glucocaine受损的胰岛素，但不是乙酰胆碱诱导的血管舒张，这是恢复TUDCA。LNAME（一氧化氮合酶抑制剂）取消胰岛素诱导的血管舒张在控制或抵抗素治疗的主动脉环。此外，TUDCA还可抑制BMPs诱导的促炎细胞因子肿瘤核因子（TNF）α和白细胞介素（IL）-1 β mRNA的表达。结论：我们的研究结果支持了这样一种观点，即内质网应激可能在血管胰岛素信号转导和胰岛素作用的受损中起重要作用。减轻内质网应激可能是肥胖和胰岛素抵抗相关疾病中心血管疾病预防和治疗的新策略。
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.
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DOI：
10.1016/j.bbrc.2017.09.020
发表时间：
2017-11-04
影响因子：
3.1
作者：
Guo, Qian;Jin, Sanli;Gu, Ning
通讯作者：
Gu, Ning
影响因子：
7.7
作者：
King GL;Park K;Li Q
通讯作者：
Li Q
影响因子：
11.4
作者：
Luchetti F;Crinelli R;Cesarini E;Canonico B;Guidi L;Zerbinati C;Di Sario G;Zamai L;Magnani M;Papa S;Iuliano L
通讯作者：
Iuliano L
影响因子：
7.7
作者：
Gentile, Maria Teresa;Vecchione, Carmine;Lembo, Giuseppe
通讯作者：
Lembo, Giuseppe
影响因子：
6
作者：
Ghemrawi R;Battaglia-Hsu SF;Arnold C
通讯作者：
Arnold C