Background: Chronic diabetes accelerates vascular dysfunction often resulting in cardiomyopathy but underlying mechanisms remain unclear. Recent studies have shown that the deregulated unfolded protein response (UPR) dependent on highly conserved IRE1α-spliced X-box- binding protein (XBP1s) and the resulting endoplasmic reticulum stress (ER-Stress) plays a crucial role in the occurrence and development of diabetic cardiomyopathy (DCM). In the present study, we determined whether targeting MAPK/ERK pathway using MEK inhibitor U0126 could ameliorate DCM by regulating IRE1α-XBP1s pathway./nMethod: Three groups of 8-week-old C57/BL6J mice were studied: one group received saline injection as control (n=8) and two groups were made diabetic by streptozotocin (STZ) (n=10 each). 18 weeks after STZ injection and stable hyperglycemia, one group had saline treatment while the second group was treated with U0126 (1mg/kg/day), 8 weeks later, all groups were sacrificed. Cardiac function/histopathological changes were determined by echocardiogram examination, Millar catheter system, hematoxylin-eosin staining and western blot analysis. H9C2 cardiomyocytes were employed for in vitro studies./nResults: Echocardiographic, hemodynamic and histological data showed overt myocardial hypertrophy and worsened cardiac function in diabetic mice. Chronic diabetic milieu enhanced SUMOylation and impaired nuclear translocation of XBP1s. Intriguingly, U0126 treatment significantly ameliorated progression of DCM, and this protective effect was achieved through enriching XBP1s' nuclear accumulation. Mechanistically, U0126 inhibited XBP1s' phosphorylation on S348 and SUMOylation on K276 promoting XBP1s' nuclear translocation. Collectively, these results identify that MEK inhibition restores XBP1s-dependent UPR and protects against diabetes-induced cardiac remodeling./nConclusion: The current study identifies previously unknown function of MEK/ERK pathway in regulation of ER-stress in DCM. U0126 could be a therapeutic target for the treatment of DCM.

中文翻译：

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MEK 抑制剂 U0126 通过限制 XBP1 的磷酸化依赖性 SUMO 化来改善糖尿病心肌病

背景：慢性糖尿病会加速血管功能障碍，经常导致心肌病，但其潜在机制仍不清楚。最近的研究表明，依赖于高度保守的 IRE1α 剪接的 X-box 结合蛋白 (XBP1s) 的去调节的未折叠蛋白反应 (UPR) 和由此产生的内质网应激 (ER-Stress) 在糖尿病心肌病（DCM）。在本研究中，我们确定了使用 MEK 抑制剂 U0126 靶向 MAPK/ERK 通路是否可以通过调节 IRE1α-XBP1s 通路来改善 DCM。/n方法：研究了三组 8 周龄 C57/BL6J 小鼠：一组接受盐水注射作为对照（n=8），两组用链脲佐菌素（STZ）制成糖尿病（每组 n=10）。STZ注射后18周血糖稳定后，一组给予生理盐水治疗，第二组给予U0126（1mg/kg/天）治疗，8周后处死各组。通过超声心动图检查、Millar 导管系统、苏木精-伊红染色和蛋白质印迹分析确定心脏功能/组织病理学变化。H9C2 心肌细胞用于体外研究。/n结果：超声心动图、血流动力学和组织学数据显示糖尿病小鼠明显的心肌肥大和心脏功能恶化。慢性糖尿病环境增强了 XBP1 的 SUMO 化和受损的核转位。有趣的是，U0126 治疗显着改善了 DCM 的进展，这种保护作用是通过丰富 XBP1s 的核积累来实现的。从机制上讲，U0126 抑制 XBP1s 在 S348 上的磷酸化和 K276 上的 SUMOylation，从而促进 XBP1s 的核转位。总的来说，这些结果表明 MEK 抑制可恢复 XBP1s 依赖性 UPR 并防止糖尿病引起的心脏重塑。/n结论：目前的研究确定了 MEK/ERK 通路在调节 DCM 中 ER 应激方面的未知功能。U0126 可能是治疗 DCM 的治疗靶点。