Melatonin reverses flow shear stress-induced injury in bone marrow mesenchymal stem cells via activation of AMP-activated protein kinase signaling

被引:57
作者
Yang, Yang [1 ,2 ]
Fan, Chongxi [3 ]
Deng, Chao [1 ]
Zhao, Lin [1 ]
Hu, Wei [2 ]
Di, Shouyin [3 ]
Ma, Zhiqiang [3 ]
Zhang, Yu [1 ]
Qin, Zhigang [1 ]
Jin, Zhenxiao [1 ]
Yan, Xiaolong [3 ]
Jiang, Shuai [4 ]
Sun, Yang [1 ,5 ]
Yi, Wei [1 ]
机构
[1] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiovasc Surg, 127 Changle West Rd, Xian 710032, Peoples R China
[2] Fourth Mil Med Univ, Dept Biomed Engn, Xian 710032, Peoples R China
[3] Fourth Mil Med Univ, Tangdu Hosp, Dept Thorac Surg, Xian 710032, Peoples R China
[4] Fourth Mil Med Univ, Dept Aerosp Med, Xian 710032, Peoples R China
[5] Fourth Mil Med Univ, Xijing Hosp, Dept Geriatr, Xian 710032, Peoples R China
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
AMP-activated protein kinase; bone marrow mesenchymal stem cells; flow shear stress; melatonin; tissue-engineered heart valve; VALVULAR HEART-DISEASE; ISCHEMIA-REPERFUSION INJURY; MYOCARDIAL-ISCHEMIA; ENDOTHELIAL DYSFUNCTION; VALVE-REPLACEMENT; OXIDATIVE STRESS; STROMAL CELLS; DIFFERENTIATION; PREVENTS; SURVIVAL;
D O I
10.1111/jpi.12306
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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 factor (TGF-), 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.
引用
收藏
页码:228 / 241
页数:14
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