Melatonin protects against chronic intermittent hypoxia-induced cardiac hypertrophy by modulating autophagy through the 5′ adenosine monophosphate-activated protein kinase pathway

Xie, Sheng; Deng, Yan; Pan, Yueying; Wang, Zhihua; Ren, Jie; Guo, Xueling; Yuan, Xiao; Shang, Jin; Liu, Huiguo

doi:10.1016/j.bbrc.2015.06.149

Cited by 50 publications

(24 citation statements)

References 41 publications

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“…Although during the last decade different studies have related melatonin with autophagy regulation in different disease models, like cardiac and brain ischemia or subarachnoid hemorrhage, kainic acid–induced toxicity, prion peptide–induced toxicity, Parkinson's disease, traumatic brain injury, or aging models, little is known about its implication in AD, and more specifically in tauopathies. Melatonin is widely known to regulate the autophagy‐lysosome machinery at very different levels .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Luengo¹,

Buendía

Fernández‐Mendívil³

et al. 2019

Journal of Pineal Research

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Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.

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Section: Discussionmentioning

confidence: 99%

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Luengo¹,

Buendía

Fernández‐Mendívil³

et al. 2019

Journal of Pineal Research

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“…Furthermore, the activation of AMPK phosphorylation inhibits BMSC apoptosis induced by ischemia and hypoxia/serum deprivation . The AMPK signaling pathway participates in melatonin‐mediated protection through various mechanisms, including attenuation of mitochondrial oxidative stress , endoplasmic reticulum stress , insulin resistance , modulation of autophagy , and especially inhibition of apoptosis . AMPK further phosphorylates acetyl‐CoA carboxylase 1 (ACC1) at Ser79 and ACC2 at Ser212, inhibiting the conversion of acetyl‐CoA to malonyl‐CoA .…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Fan

Deng

et al. 2016

Journal of Pineal Research

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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.

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“…Majority of the studies report that melatonin suppresses autophagy in cells and organisms which are exposed to different stressors, therefore reducing their injury and improving their recovery. Some reports document that melatonin may also induce or enhance autophagy [143,194,195,196,197,198,199]. The influence of melatonin on autophagy seems well conserved since this association also has been found in plants [200,201].…”

Section: Melatonin Regulates Mitochondrial Dynamicsmentioning

confidence: 99%

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

Tan

Manchester

Qin

et al. 2016

IJMS

318

256

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Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria.

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Melatonin protects against chronic intermittent hypoxia-induced cardiac hypertrophy by modulating autophagy through the 5′ adenosine monophosphate-activated protein kinase pathway

Cited by 50 publications

References 41 publications

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

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

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

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