mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1.
mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1.
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DOI：
10.1016/j.phrs.2016.06.024
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发表时间：
2016-09
影响因子：
9.3
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Wang, Qiurong;Ren, Jun
胰岛素抵抗与心血管疾病有关，但其确切机制仍不清楚。 Akt2 是 Akt 家族的重要成员，在胰岛素信号传导中发挥着重要作用。本研究旨在探讨海藻糖（一种不依赖于 mTOR 的自噬诱导剂）对 Akt2 敲除诱导的胰岛素抵抗模型中心肌功能的影响。成年 WT 和 Akt2 敲除 (Akt2−/−) 小鼠被给予海藻糖（1 mg/g/天，腹腔注射）两天，然后再给予两个月的 2% 海藻糖饮用水。评估了超声心动图和心肌力学、细胞内Ca2+特性、葡萄糖耐量和自噬。使用 TUNEL 染色、Caspase 3 测定和蛋白质印迹评估细胞凋亡和 ER 应激。检查自噬和自噬通量，重点关注 p38 丝裂原激活蛋白激酶 (MAPK)、Forkhead box O (Foxo1) 和 Akt。 Akt2 消融会损害葡萄糖耐量、心肌几何形状和功能，并伴有明显的细胞凋亡、内质网应激和自噬减弱，海藻糖治疗可改善其影响。使用巴弗洛霉素 A1 抑制溶酶体活性可消除海藻糖诱导的自噬诱导（LC3B-II 和 p62）。此外，p38 MAPK 和 Foxo1 的磷酸化在 Akt2−/− 小鼠中上调，但海藻糖减弱了其作用。 Akt2−/− 小鼠中 Akt 的磷酸化受到抑制，并且不受海藻糖的影响。体外研究结果表明，p38 MAPK 激活剂茴香霉素和 Foxo1 抑制剂（通过磷酸化）AS1842856 有效掩盖了海藻糖提供的针对 Akt2 消融的有益心肌细胞收缩反应。这些数据表明，海藻糖可以通过与 p38 MAPK 和 Foxo1 去磷酸化相关的自噬，在不影响 Akt 磷酸化的情况下，挽救胰岛素抵抗诱导的心肌收缩缺陷和细胞凋亡。
Insulin resistance is associated with cardiovascular diseases although the precise mechanisms remain elusive. Akt2, a critical member of the Akt family, plays an essential role in insulin signaling. This study was designed to examine the effect of trehalose, an mTOR-independent autophagy inducer, on myocardial function in an Akt2 knockout-induced insulin resistance model. Adult WT and Akt2 knockout (Akt2−/−) mice were administered trehalose (1 mg/g/day, i.p.) for two days and were then given 2% trehalose in drinking water for two more months. Echocardiographic and myocardial mechanics, intracellular Ca2+ properties, glucose tolerance, and autophagy were assessed. Apoptosis and ER stress were evaluated using TUNEL staining, Caspase 3 assay and Western blot. Autophagy and autophagy flux were examined with a focus on p38 mitogen activated protein kinase (MAPK), Forkhead box O (Foxo1) and Akt. Akt2 ablation impaired glucose tolerance, myocardial geometry and function accompanied with pronounced apoptosis, ER stress and dampened autophagy, the effects of which were ameliorated by trehalose treatment. Inhibition of lysosomal activity using bafilomycin A1 negated trehalose–induced induction of autophagy (LC3B–II and p62). Moreover, phosphorylation of p38 MAPK and Foxo1 were upregulated in Akt2−/− mice, the effect of which was attenuated by trehalose. Phosphorylation of Akt was suppressed in Akt2−/− mice and was unaffected by trehalose. In vitro findings revealed that the p38 MAPK activator anisomycin and the Foxo1 inhibitor (through phosphorylation) AS1842856 effectively masked trehalose-offered beneficial cardiomyocyte contractile response against Akt2 ablation. These data suggest that trehalose may rescue against insulin resistance-induced myocardial contractile defect and apoptosis, via autophagy associated with dephosphorylation of p38 MAPK and Foxo1 without affecting phosphorylation of Akt.
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影响因子：
4
作者：
Cui, Yong;Lin, Jing;Lu, Yicheng
通讯作者：
Lu, Yicheng
影响因子：
3.4
作者：
Kara, N. Z.;Toker, L.;Einat, H.
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影响因子：
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作者：
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Fernandez-Estevez MA;Casarejos MJ;López Sendon J;Garcia Caldentey J;Ruiz C;Gomez A;Perucho J;de Yebenes JG;Mena MA
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Mena MA
影响因子：
3.5
作者：
Davies, JE;Sarkar, S;Rubinsztein, DC
通讯作者：
Rubinsztein, DC