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Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling
Journal of Pineal Research ( IF 10.3 ) Pub Date : 2017-06-09 , DOI: 10.1111/jpi.12418
Mingming Zhang 1, 2 , Jie Lin 2 , Shanjie Wang 2 , Zheng Cheng 1, 2 , Jianqiang Hu 1, 2 , Tingting Wang 1, 2 , Wanrong Man 1, 2 , Tao Yin 2 , Wenyi Guo 2 , Erhe Gao 3 , Russel J. Reiter 4 , Haichang Wang 1, 2 , Dongdong Sun 1, 2
Affiliation  

This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1−/−) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1−/− mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3‐II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.

中文翻译:

褪黑素通过Mst1 / Sirt3信号传导预防糖尿病性心肌病

这项研究调查了褪黑激素对糖尿病性心肌病(DCM)的影响并确定了潜在的机制。超声心动图显示褪黑素可显着缓解DCM的不良左心室重塑并减轻心脏功能障碍。该机制归因于自噬增加,细胞凋亡减少和线粒体功能障碍减轻。此外,褪黑激素抑制Mst1磷酸化并促进DCM中Sirt3的表达。这些结果表明褪黑激素可能通过Mst1 / Sirt3信号传导发挥其作用。为了验证此假设,使用Mst1转基因(Mst1 Tg)和Mst1敲除(Mst1 -/-的DCM模型)小鼠被构建。如预期的那样,褪黑激素在遭受DCM损伤的Mst1 Tg小鼠中增加了自噬,减少了细胞凋亡并改善了线粒体的生物发生,而对Mst1 -/-小鼠却没有影响。此外,对培养的新生小鼠心肌细胞进行了模拟糖尿病研究,以探讨其参与的机制。褪黑激素的施用促进了自噬通量,如存在杆状霉素A1时LC3-II升高和p62表达降低所证明。结果表明,褪黑激素可通过上调自噬,限制细胞凋亡以及调节线粒体完整性和生物发生来缓解DCM中的心脏重塑和功能障碍。这些机制与Mst1 / Sirt3信令相关。
更新日期:2017-06-09
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