Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China; Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.
Cell Signal. 2018 Jul;47:88-100. doi: 10.1016/j.cellsig.2018.03.012. Epub 2018 Mar 28.
Melatonin and its metabolites have been demonstrated to modulate the glucose, dyslipidemia and other metabolic disorders. This study aimed to explore a novel mechanism responsible for diabetic cardiomyopathy development, and also validated whether melatonin played a protective role in repairing damaged heart in the diabetes setting. Our data demonstrated that spleen tyrosine kinase (Syk) was activated by chronic high-glucose stimulus and contributed to the development of diabetic cardiomyopathy. However, genetic ablation of Syk or supplementation of melatonin to inhibit Syk activation improved diabetic myocardial function, reduced cardiac fibrosis and preserved cardiomyocytes viability. Mechanistically, activated Syk repressed the expression and activity of mitochondrial complex I (COX-1), unfortunately evoking mitochondrial and/or cellular ROS overproduction. Subsequently, excessive superoxide facilitated SERCA peroxidation which failed to re-uptake the cytoplasmic calcium back into endoplasmic reticulum (ER), leading to cellular calcium overload. Finally, activated oxidative stress and calcium overload collectively promoted the high-glucose-induced cardiomyocytes death via caspase-9-related mitochondrial apoptosis and caspase-12-involved ER apoptosis, respectively. Interestingly, inhibition of Syk via Syk genetic ablation or melatonin administration blocked Syk/COX-1/SERCA signalling pathways, and thus abolished mitochondrial- and ER-mediated cardiomyocyte death in the setting of diabetes. Based on these results, we suggest a novel pathway by which high-glucose stimulus induces diabetic cardiomyopathy is possibly through an activation of Syk/COX-1/SERCA axis which could be abrogated by melatonin treatment.
褪黑素及其代谢产物已被证明可调节葡萄糖、血脂异常和其他代谢紊乱。本研究旨在探索一种负责糖尿病心肌病发展的新机制，并验证褪黑素在糖尿病环境中是否对修复受损心脏发挥保护作用。我们的数据表明，慢性高葡萄糖刺激会激活脾酪氨酸激酶（Syk），并导致糖尿病心肌病的发展。然而，Syk 的基因缺失或褪黑素的补充以抑制 Syk 激活，改善了糖尿病心肌功能，减少了心脏纤维化并保护了心肌细胞活力。在机制上，激活的 Syk 抑制了线粒体复合物 I（COX-1）的表达和活性，不幸的是引发了线粒体和/或细胞 ROS 的过度产生。随后，过量的超氧化物促进 SERCA 过氧化，无法将细胞质中的钙重新摄取回内质网（ER），导致细胞内钙超载。最后，激活的氧化应激和钙超载通过 caspase-9 相关的线粒体凋亡和 caspase-12 相关的内质网凋亡分别共同促进高葡萄糖诱导的心肌细胞死亡。有趣的是，通过 Syk 基因缺失或褪黑素给药抑制 Syk，阻断了 Syk/COX-1/SERCA 信号通路，从而消除了糖尿病状态下线粒体和 ER 介导的心肌细胞死亡。基于这些结果，我们提出了一种新的途径，即高葡萄糖刺激通过激活 Syk/COX-1/SERCA 轴诱导糖尿病心肌病，而褪黑素治疗可以阻断该途径。
