Melatonin reverses flow shear stress-induced injury in bone marrow mesenchymal stem cells via activation of AMP-activated protein kinase signaling
Melatonin reverses flow shear stress-induced injury in bone marrow mesenchymal stem cells via activation of AMP-activated protein kinase signaling
复制标题
褪黑激素通过激活 AMP 激活的蛋白激酶信号逆转流动剪切应力诱导的骨髓间充质干细胞损伤
DOI：
10.1111/jpi.12306
复制
发表时间：
2016
影响因子：
10.3
通讯作者：
Yi Wei
中科院分区：
文献类型：
--
作者：
Yang Yang;Fan Chongxi;Deng Chao;Zhao Lin;Hu Wei;Di Shouyin;Ma Zhiqiang;Zhang Yu;Qin Zhigang;Jin Zhenxiao;Yan Xiaolong;Jiang Shuai;Sun Yang;Yi Wei
组织工程心脏瓣膜（TEHVs）是一种很有前景的治疗瓣膜性心脏病的方法，尽管其应用受到高血流剪切应力（FSS）的限制。褪黑素具有广泛的生理功能，目前正处于临床研究阶段，以扩大应用范围；此外，已经报道了对心血管系统的广泛保护作用。在这项研究中，我们研究了褪黑素补充对FSS诱导的骨髓间充质干细胞（BMSCs）损伤的保护作用，并阐明了这一过程的潜在机制。褪黑素以浓度依赖的方式显著降低BMSC凋亡死亡，同时增加转化生长因子β（TGF‐β）、碱性成纤维细胞生长因子（bFGF）、血管内皮生长因子（VEGF）、血小板衍生生长因子（PDGF）和B细胞淋巴瘤2 （Bcl2）的水平，降低Bcl‐2相关X蛋白（Bax）、p53上调凋亡调节剂（PUMA）和caspase 3的水平。值得注意的是，褪黑素通过上调单磷酸腺苷活化蛋白激酶（AMPK）的磷酸化来发挥其保护作用，AMPK可促进乙酰辅酶a羧化酶（ACC）的磷酸化。进一步的分子实验表明，作为褪黑激素受体的非选择性拮抗剂，luzindole阻断了褪黑激素的抗FSSI损伤（anti - FSSI）作用。化合物C对AMPK的抑制也抵消了褪黑素的保护作用，表明褪黑素通过AMPK依赖性途径逆转骨髓间充质干细胞中的FSSI。总之，我们的研究结果表明，褪黑激素通过激活褪黑激素受体和AMPK/ACC信号通路，有助于改善FSS诱导的BMSC损伤。我们的研究结果可能为设计更有效的策略提供基础，以促进患者使用tehc。
Tissue‐engineered heart valves (TEHVs) are a promising treatment for valvular heart disease, although their application is limited by high flow shear stress (FSS). Melatonin has a wide range of physiological functions and is currently under clinical investigation for expanded applications; moreover, extensive protective effects on the cardiovascular system have been reported. In this study, we investigated the protection conferred by melatonin supplementation against FSS‐induced injury in bone marrow mesenchymal stem cells (BMSCs) and elucidated the potential mechanism in this process. Melatonin markedly reduced BMSC apoptotic death in a concentration‐dependent manner while increasing the levels of transforming growth factorβ(TGF‐β), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF) and B‐cell lymphoma 2 (Bcl2), and decreasing those of Bcl‐2‐associated X protein (Bax), p53 upregulated modulator of apoptosis (PUMA), and caspase 3. Notably, melatonin exerted its protective effects by upregulating the phosphorylation of adenosine monophosphate‐activated protein kinase (AMPK), which promotes acetyl‐CoA carboxylase (ACC) phosphorylation. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked the anti‐FSS injury (anti‐FSSI) effects of melatonin. Inhibition of AMPK by Compound C also counteracted the protective effects of melatonin, suggesting that melatonin reverses FSSI in BMSCs through the AMPK‐dependent pathway. Overall, our findings indicate that melatonin contributes to the amelioration of FSS‐induced BMSC injury by activating melatonin receptors and AMPK/ACC signaling. Our findings may provide a basis for the design of more effective strategies that promote the use of TEHCs in patients.