The Emerging Role of Sestrin2 in Cell Metabolism, and Cardiovascular and Age-Related Diseases

Sun, Wanqing; Wang, Yishi; Zheng, Yang; Quan, Nanhu

doi:10.14336/ad.2019.0320

Cited by 51 publications

(56 citation statements)

References 109 publications

(143 reference statements)

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“…Sestrins are highly conserved stress response proteins; the three sestrins (Sesn1–3) expressed in mammals are encoded by three independent genomic loci. Sestrins are mainly induced by hypoxia, oxidative stress, DNA damage, and other stress [ [26] , [27] , [28] , [29] ]; they have also been shown to mediate exercise benefits and adaptations in both fly and mouse models [ 30 ]. Recent studies have shown that Sesn2 can inhibit mTORC1 through 5′-adenosine monophosphate-activated protein kinase (AMPK)-dependent or -independent pathways [ 27 , 28 , [31] , [32] , [33] , [34] ].…”

Section: Introductionmentioning

confidence: 99%

Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Quan

Zhang

et al. 2020

Redox Biology

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Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4–6 months), aged WT (24–26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4–6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger hearts and impaired cardiac function, compared with young WT mice. Augmented phosphorylation of mTOR and downstream effectors; damaged mitochondria and elevated redox markers, as well as and impaired glucose and fatty acid oxidation were observed in aged WT and Y-Sesn2 KO hearts. A pressure overload-induced interaction between Sesn2 and GTPase-activating protein activity toward Rags 2 (GATOR2), which positively regulates mTORC1, was impaired in aged WT hearts. Adeno-associated virus 9–Sesn2 treatment rescued Sesn2 expression, attenuated mTORC1 activation, and increased pressure overload tolerance in aged WT and Y-Sesn2 KO hearts. These results indicated that cardiac Sesn2 acts as a pressure overload sensor for mTORC1. Furthermore, Sesn2 deficiency may cause increased sensitivity to hypertrophy in elderly individuals.

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Section: Introductionmentioning

confidence: 99%

Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Quan

Zhang

et al. 2020

Redox Biology

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“…Sestrin2 is suggested to be associated with aging and age-related diseases [ 10 , 11 ], and plasma sestrin2 levels were reported to positively correlate with age [ 12 , 17 ]. In our study, sestrin2 levels also correlated with age ( r = 0.29).…”

Section: Discussionmentioning

confidence: 99%

“…Atherosclerosis is recognized to be associated with inflammation with oxidative stress [ 1 , 2 ], and sestrin2 is suggested to play a protective role against atherosclerotic disease [ 10 , 11 ]. Regarding the association between sestrin2 and atherosclerotic disease, one small study [ 12 ] recently reported that plasma sestrin2 levels were higher in 44 patients with stable CAD than in 35 patients without CAD.…”

Section: Introductionmentioning

confidence: 99%

Association between Plasma Sestrin2 Levels and the Presence and Severity of Coronary Artery Disease

et al. 2020

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Aims. Atherosclerotic disease, such as coronary artery disease (CAD), is recognized to be associated with inflammation and oxidative stress. We investigated the association between CAD and plasma levels of sestrin2 which is one of the stress-inducible antioxidant proteins. Methods. We measured plasma sestrin2 levels in 304 patients undergoing elective coronary angiography. The severity of CAD was represented as the numbers of >50% stenotic coronary vessels and segments and the severity score. Results. CAD was found in 175 patients, of whom 73 had 1-vessel (1-VD), 59 had 2-vessel (2-VD), and 43 had 3-vessel disease (3-VD). Plasma sestrin2 levels were significantly higher in 175 patients with CAD than in 129 without CAD (median 16.4 vs. 14.2 ng/mL, P<0.05). A stepwise increase in sestrin2 levels was found depending on the number of >50% stenotic coronary vessels: 14.2 in CAD(-), 15.4 in 1-VD, 17.3 in 2-VD, and 17.7 ng/mL in3-VD (P<0.05). High sestrin2 level (>16.0 ng/mL) was present in 38% of patients with CAD(-), 47% of 1-VD, 66% of 2-VD, and 53% of 3-VD (P<0.005). Sestrin2 levels significantly, but weakly, correlated with the number of >50% stenotic segments and the severity score (rs=0.12 and rs=0.13, P<0.05). In the multivariate analysis, sestrin2 levels were a significant factor associated with CAD independent of atherosclerotic risk factors. The odds ratio for CAD was 1.79 (95%CI=1.09‐2.95) for high sestrin2 level of >16.0 ng/mL (P<0.025). Conclusions. Plasma sestrin2 levels in patients with CAD were found to be high and to be associated with the severity of CAD. High sestrin2 levels in patients with CAD may reflect a protective response against the progression of CAD.

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“…Aging or shortening of lifespan is closely connected with the exposure to oxidative stress, DNA damaging agents, losing immunity, and metabolic dysregulation (Lee et al, 2013;Wei Y. et al, 2015;Srivastava, 2017;Dalina et al, 2018;Fan et al, 2020;Sun et al, 2020). As human life expectancy has extended, the importance of healthy aging or elderly health is increasing and drawing significant attention among the general public.…”

Section: Sestrins In Environmental Stress and Agingmentioning

confidence: 99%

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Fay

Cyuzuzo

et al. 2020

Front. Cell Dev. Biol.

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Proper timely management of various external and internal stresses is critical for metabolic and redox homeostasis in mammals. In particular, dysregulation of mechanistic target of rapamycin complex (mTORC) triggered from metabolic stress and accumulation of reactive oxygen species (ROS) generated from environmental and genotoxic stress are well-known culprits leading to chronic metabolic disease conditions in humans. Sestrins are one of the metabolic and environmental stress-responsive groups of proteins, which solely have the ability to regulate both mTORC activity and ROS levels in cells, tissues and organs. While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. In this review, we discuss recent studies that investigated and manipulated Sestrins-mediated stress signaling pathways in metabolic and environmental health. Sestrins as an emerging dynamic group of stress-sensor proteins are drawing a spotlight as a preventive or therapeutic mechanism in both metabolic stress-associated pathologies and aging processes at the same time.

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The Emerging Role of Sestrin2 in Cell Metabolism, and Cardiovascular and Age-Related Diseases

Cited by 51 publications

References 109 publications

Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Association between Plasma Sestrin2 Levels and the Presence and Severity of Coronary Artery Disease

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

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