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

Abstract

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 β (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.

• Authors: Yang Yang, Chongxi Fan, Chao Deng, Lin Zhao, Wei Hu, Shouyin Di, Zhiqiang Ma, Yu Zhang, Zhigang Qin, Zhenxiao Jin, Xiaolong Yan, Shuai Jiang, Yang Sun, Wei Yi
• Journal: Journal of pineal research (J Pineal Res) Vol. 60 Issue 2 Pg. 228-41 (Mar 2016) ISSN: 1600-079X [Electronic] England
• PMID: 26707568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• AMP-Activated Protein Kinases
• Melatonin

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis (drug effects)
• Bone Marrow Cells (enzymology, pathology)
• Gene Expression Regulation (drug effects)
• Male
• Melatonin (pharmacology)
• Mesenchymal Stem Cells (enzymology, pathology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Stress, Mechanical
• Stress, Physiological (drug effects)