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.

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

“…Moreover, we recently demonstrated that melatonin reduced flow shear stress (FSS)-induced bone marrow mesenchymal stem cell injury by activating melatonin membrane receptors and AMPK signaling50. Kunst et al .…”

Dietary Sources and Bioactivities of Melatonin

“…Moreover, melatonin has been reported to protect cardiomyocytes and blood vessels against fibrosis necrosis and vasculitis in radiation-induced heart disease in rats when administrated at 50 mg/kg [254]. Furthermore, melatonin was demonstrated to dose-dependently reduce flow shear stress-induced injury in bone marrow mesenchymal stem cells (BM-MSCs) through the activation of melatonin receptors and adenosine monophosphate activated protein kinase (AMPK)/ACC (acetyl-CoA carboxylase) signaling, which could benefit the patients with valvular heart disease [255]. …”

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

“…Western blotting was performed as previously described [34]. Briefly, the treated hearts and cells were collected and washed with ice-cold PBS prior to the addition of lysis buffer (containing 20 mM Tris-HCl at the pH of 7.5; 150 mM NaCl; 1 mM EDTA; 1 mM EGTA; 1% Triton; 2.5 mM sodium pyrophosphate; 1 mM β-glycerophosphate; 1 mM Na 3 VO 4 ; and 1 μg/mL leupeptin).…”