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 ( TEHV s) 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 ( BMSC s) 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 BMSC s 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 TEHC s in patients.