Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway

Chen, Wei Ren; Yang, Jia; Liu, Fang; Shen, Xue; Zhou, Yu Jie

doi:10.1016/j.yexcr.2020.111883

Cited by 34 publications

(30 citation statements)

References 26 publications

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“…The activation of AMPK with melatonin, metformin, intermedin 1-53 or MOTS-c ameliorated VCN whereas the AMPK inhibitor compound C worsened VCN. Melatonin ameliorated VSMC calcification in vitro through the activation of AMPK [58]. In line with these findings, metformin ameliorated VSMC calcification in vitro through AMPK activation [59].…”

Section: Stimulating Autophagy In Vascular Calcification By Activatinsupporting

confidence: 71%

“…Indeed, there are multiple lines of evidence supporting AMPK as an anti-VSMC calcification mechanism. Melatonin, metformin, ghrelin, intermedin1-53 and MOTS-c have all been demonstrated to ameliorate VCN in vitro and/or in vivo, accredited due to their ability to increase AMPK activity [58][59][60][61][62]. The latter enhances YAP glycosylation.…”

Section: Autophagy Protects Against Vascular Calcificationmentioning

confidence: 99%

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The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

Neutel

Hendrickx

Martinet

et al. 2020

IJMS

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Background: Autophagy is a highly conserved catabolic homeostatic process, crucial for cell survival. It has been shown that autophagy can modulate different cardiovascular pathologies, including vascular calcification (VCN). Objective: To assess how modulation of autophagy, either through induction or inhibition, affects vascular and valvular calcification and to determine the therapeutic applicability of inducing autophagy. Data sources: A systematic review of English language articles using MEDLINE/PubMed, Web of Science (WoS) and the Cochrane library. The search terms included autophagy, autolysosome, mitophagy, endoplasmic reticulum (ER)-phagy, lysosomal, calcification and calcinosis. Study characteristics: Thirty-seven articles were selected based on pre-defined eligibility criteria. Thirty-three studies (89%) studied vascular smooth muscle cell (VSMC) calcification of which 27 (82%) studies investigated autophagy and six (18%) studies lysosomal function in VCN. Four studies (11%) studied aortic valve calcification (AVCN). Thirty-four studies were published in the time period 2015–2020 (92%). Conclusion: There is compelling evidence that both autophagy and lysosomal function are critical regulators of VCN, which opens new perspectives for treatment strategies. However, there are still challenges to overcome, such as the development of more selective pharmacological agents and standardization of methods to measure autophagic flux.

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Section: Stimulating Autophagy In Vascular Calcification By Activatinsupporting

confidence: 71%

Section: Autophagy Protects Against Vascular Calcificationmentioning

confidence: 99%

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

Neutel

Hendrickx

Martinet

et al. 2020

IJMS

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“…The effect of melatonin on the autophagic process is controversial. Some studies have shown that melatonin can enhance autophagy, 46,47 while others have found that melatonin plays a beneficial role in neurodegeneration by inhibiting the autophagic process via mechanisms such as preventing 1-methyl-4-phenylpyridinium-induced cell death, methamphetamine-induced autophagy, and CDK5-mediated autophagy. [48][49][50] In our present study, we found that melatonin treatment significantly suppressed excessive neuronal autophagy both in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Che

Yang

et al. 2020

FASEB j.

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Diabetes mellitus (DM) patients are at a higher risk of developing brain injury characterized by neuronal death. Melatonin, a hormone produced by the pineal gland, exerts neuroprotective effects against brain damage. However, the effect of melatonin on diabetes‐induced brain injury has not been elucidated. This study was to evaluate the role of melatonin against neuronal death in DM and to elucidate the underlying mechanisms. Herein, we found that melatonin administration significantly alleviated the neuronal death in both streptozotocin (STZ)‐induced diabetic mice and high glucose (HG)‐treated neuronal cells. Melatonin inhibited neuronal pyroptosis and excessive autophagy, as evidenced by decreased levels of NLRP3, cleaved caspase‐1, GSDMD‐N, IL‐1β, LC3, Beclin1, and ATG12 both in vivo and in vitro. MicroRNA‐214‐3p (miR‐214‐3p) was decreased in DM mice and HG‐treated cells, and such a downregulation was corrected by melatonin, which was accompanied by repression of caspase‐1 and ATG12. Furthermore, downregulation of miR‐214‐3p abrogated the anti‐pyroptotic and anti‐autophagic actions of melatonin in vitro. Our results indicate that melatonin exhibits a neuroprotective effect by inhibiting neuronal pyroptosis and excessive autophagy through modulating the miR‐214‐3p/caspase‐1 and miR‐214‐3p/ATG12 axes, respectively, and it might be a potential agent for the treatment of brain damage in the setting of DM.

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“…In addition, melatonin has been shown to attenuate the progression of atherosclerosis by inducing mitophagy and reducing inflammasome activation [14]. In our previous study, melatonin protected VSMCs against calcification by activating autophagy via the AMPK pathway [15]. Importantly, melatonin not only reduced calcium deposition and osteogenic differentiation but also suppressed apoptosis and inflammation [16].…”

Section: Introductionmentioning

confidence: 96%

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

Chen

Zhou

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Mitochondrial fusion/mitophagy plays a role in cardiovascular calcification. Melatonin has been shown to protect against cardiovascular disease. This study sought to explore whether melatonin attenuates vascular calcification by regulating mitochondrial fusion/mitophagy via the AMP-activated protein kinase/optic atrophy 1 (AMPK/OPA1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red S staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2), mitofusin 2 (Mfn2), mito-light chain 3 (mito-LC3) II, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated in response to melatonin, whereas Mfn2 and mito-LC3II were enhanced and accompanied by decreased mitochondrial superoxide levels. Melatonin also maintained mitochondrial function and promoted mitochondrial fusion/mitophagy via the OPA1 pathway. However, OPA1 deletion abolished the protective effects of melatonin on VSMC calcification. Melatonin treatment significantly increased p-AMPK and OPA1 protein expression, whereas treatment with compound C ablated the observed benefits of melatonin treatment. Collectively, our results demonstrate that melatonin protects VSMCs against calcification by promoting mitochondrial fusion/mitophagy via the AMPK/OPA1 pathway.

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Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway

Cited by 34 publications

References 26 publications

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

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