Melatonin inhibits vascular smooth muscle cell proliferation and apoptosis through upregulation of Sestrin2

Lee, Seunghyeong; Byun, Jun‐Kyu; Park, Mihyang; Kim, Sung Woo; Lee, Sung‐Woo; Kim, Jung‐Guk; Lee, Inkyu; Choi, Youn‐Hee; Park, Keun Gyu

doi:10.3892/etm.2020.8638

Cited by 14 publications

(13 citation statements)

References 28 publications

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“…Sestrin2 inhibits mTORC1 in VSMCs to suppress their excessive proliferation. Furthermore, Sestrin2 inhibits ROS production and prevents excessive apoptosis of VSMCs [48]. Likewise, it was shown that Sestrin2 can upreg-ulate Nrf2 to protect VSMCs against Angiotensin-II-(Ang-II-) induced apoptosis (Figures 1 and 2) [49].…”

Section: Sestrin2 In Cardiovascular Diseasesmentioning

confidence: 90%

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

Ala

Eftekhar

2021

Oxidative Medicine and Cellular Longevity

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Sestrin2 is a stress-inducible metabolic regulator and a conserved antioxidant protein which has been implicated in the pathogenesis of several diseases. Sestrin2 can protect against atherosclerosis, heart failure, hypertension, myocardial infarction, stroke, spinal cord injury neurodegeneration, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, acute kidney injury (AKI), chronic kidney disease (CKD), and pulmonary inflammation. Oxidative stress and cellular damage signals can alter the expression of Sestrin2 to compensate for organ damage. Different stress signals such as those mediated by P53, Nrf2/ARE, HIF-1α, NF-κB, JNK/c-Jun, and TGF-β/Smad signaling pathways can induce Sestrin2 expression. Subsequently, Sestrin2 activates Nrf2 and AMPK. Furthermore, Sestrin2 is a major negative regulator of mTORC1. Sestrin2 indirectly regulates the expression of several genes and reprograms intracellular signaling pathways to attenuate oxidative stress and modulate a large number of cellular events such as protein synthesis, cell energy homeostasis, mitochondrial biogenesis, autophagy, mitophagy, endoplasmic reticulum (ER) stress, apoptosis, fibrogenesis, and lipogenesis. Sestrin2 vigorously enhances M2 macrophage polarization, attenuates inflammation, and prevents cell death. These alterations in molecular and cellular levels improve the clinical presentation of several diseases. This review will shed light on the beneficial effects of Sestrin2 on several diseases with an emphasis on underlying pathophysiological effects.

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Section: Sestrin2 In Cardiovascular Diseasesmentioning

confidence: 90%

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

Ala

Eftekhar

2021

Oxidative Medicine and Cellular Longevity

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“…Western blot analysis was performed as previously described [ 44 ]. Proteins in cell lysates were separated by SDS-PAGE and transferred to PVDF membranes (Millipore, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

Park

Kim

Lee

et al. 2021

IJMS

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Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

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“…Other chemical compounds such as resveratrol and melatonin possessing pleiotropic effects like antioxidancy or anti-inflammation were studied based on their capability of upregulating sestrin2 in various disease models [135][136][137]. Resveratrol is a naturally occurring polyphenol that is abundant in grape seeds and skin [138,139].…”

Section: Medications or Chemical Compounds Capable Of Altering Sestrin2 Expressionmentioning

confidence: 99%

“…These properties of melatonin underline the possibility for future clinical use in numerous disorders, including neurodegeneration [149]. It was shown that melatonin can inhibit proliferation and apoptosis in the vascular smooth muscle through upregulation of sestrin2, which may be important in preventing atherosclerosis and restenosis of vessel lumen [135]. It would be interesting to know the effect of sestrin2 expression under melatonin treatment in a stressful condition, such as in Aβ-induced neurotoxicity.…”

Section: Medications or Chemical Compounds Capable Of Altering Sestrin2 Expressionmentioning

confidence: 99%

Potential Roles of Sestrin2 in Alzheimer’s Disease: Antioxidation, Autophagy Promotion, and Beyond

et al. 2021

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Alzheimer's disease (AD) is the most common age-related neurodegenerative disease. It presents with progressive memory loss, worsens cognitive functions to the point of disability, and causes heavy socioeconomic burdens to patients, their families, and society as a whole. The underlying pathogenic mechanisms of AD are complex and may involve excitotoxicity, excessive generation of reactive oxygen species (ROS), aberrant cell cycle reentry, impaired mitochondrial function, and DNA damage. Up to now, there is no effective treatment available for AD, and it is therefore urgent to develop an effective therapeutic regimen for this devastating disease. Sestrin2, belonging to the sestrin family, can counteract oxidative stress, reduce activity of the mammalian/mechanistic target of rapamycin (mTOR), and improve cell survival. It may therefore play a crucial role in neurodegenerative diseases like AD. However, only limited studies of sestrin2 and AD have been conducted up to now. In this article, we discuss current experimental evidence to demonstrate the potential roles of sestrin2 in treating neurodegenerative diseases, focusing specifically on AD. Strategies for augmenting sestrin2 expression may strengthen neurons, adapting them to stressful conditions through counteracting oxidative stress, and may also adjust the autophagy process, these two effects together conferring neuronal resistance in cases of AD.

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Melatonin inhibits vascular smooth muscle cell proliferation and apoptosis through upregulation of Sestrin2

Cited by 14 publications

References 28 publications

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

Potential Roles of Sestrin2 in Alzheimer’s Disease: Antioxidation, Autophagy Promotion, and Beyond

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