Insulin decreases myocardial adiponectin receptor 1 expression via PI3K/Akt and FoxO1 pathway
Insulin decreases myocardial adiponectin receptor 1 expression via PI3K/Akt and FoxO1 pathway
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胰岛素通过 PI3K/Akt 和 FoxO1 途径降低心肌脂联素受体 1 表达
DOI：
10.1093/cvr/cvr273
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发表时间：
2012-01-01
影响因子：
10.8
通讯作者：
Wu, Li-Ling
中科院分区：
文献类型：
--
作者：
Cui, Xiao-Bing;Wang, Cheng;Wu, Li-Ling
脂联素被认为是一种重要的脂肪因子，具有预防糖尿病、动脉粥样硬化和心血管疾病的作用。由于脂联素受体（AdipoRs）是脂联素信号级联中的关键组分，我们研究了胰岛素对心肌AdipoRs表达的影响，并探讨了可能的分子机制。方法和结果高胰岛素血症大鼠模型通过输注胰岛素（1 U/天）诱导28天：血清和心肌脂联素水平升高，骨骼肌和心肌AdipoR 1表达和AMP活化蛋白激酶（AMPK）磷酸化降低。在原代培养的新生大鼠心室肌细胞（NRVMs）中，胰岛素降低AdipoR 1表达，但不降低AdipoR 2表达和AMPK磷酸化;高糖对AdipoRs表达无影响。Akt和细胞外信号调节激酶1/2（ERK 1/2）磷酸化在胰岛素治疗的心脏和NRVM中增加。P13 K抑制剂LY 294002和Akt 1/2激酶抑制剂可阻断胰岛素诱导的AdipoR 1表达降低和AMPK磷酸化，但ERK 1/2激酶（MEK）抑制剂PD 98059和U 0126不能阻断。胰岛素诱导叉头/翼螺旋盒基因组O-1（FoxO 1）磷酸化和易位从细胞核到胞质溶胶，这是阻断LY 294002。FoxO 1小干扰RNA降低AdipoR 1表达和AMPK磷酸化。在电泳迁移率改变实验和染色质免疫沉淀实验中，FoxO 1在体外和活细胞中均与AdipoR 1启动子-167 ~-157bp的推定位点结合;结论胰岛素通过PI 3 K/Akt和FoxO 1途径抑制心肌细胞AdipoR 1的表达，FoxO 1通过直接与AdipoR 1的启动子结合来介导AdipoR 1的转录。
Aims Adiponectin is considered an important adipokine protecting against diabetes, atherosclerosis, and cardiovascular disease. Because adiponectin receptors (AdipoRs) are critical components in the adiponectin signalling cascade, we investigated the effect of insulin on the expression of myocardial AdipoRs and explored the possible molecular mechanism.Methods and results The hyperinsulinaemia rat model was induced by infusion of insulin (1 U/day) for 28 days: serum and myocardial adiponectin levels were increased, and skeletal muscle and myocardial AdipoR1 expression and AMP-activated protein kinase (AMPK) phosphorylation were decreased. In primary cultured neonatal rat ventricular myocytes (NRVMs), insulin decreased AdipoR1 but not AdipoR2 expression and AMPK phosphorylation; high glucose had no affect on AdipoRs expression. Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased in insulin-treated hearts and in NRVMs. P13K inhibitor LY294002 and Akt1/2 kinase inhibitor but not the ERK1/2 kinase (MEK) inhibitors PD98059 and U0126 blocked the insulin-induced reduction in AdipoR1 expression and AMPK phosphorylation. Insulin induced forkhead/winged helix box gene group O-1 (FoxO1) phosphorylation and translocation from the nucleus to the cytosol, and this was blocked by LY294002. FoxO1 small interfering RNA reduced AdipoR1 expression and AMPK phosphorylation. In electrophoretic mobility shift assay and chromatin immunoprecipitation, FoxO1 bound to the putative site from -167 to -157 bp of the AdipoR1 promoter both in vitro and in living cells; insulin suppressed this binding, which was blocked by LY294002.Conclusion Insulin inhibits myocardial AdipoR1 expression via PI3K/Akt and FoxO1 pathways, and FoxO1 mediates AdipoR1 transcription by binding to its promoter directly.