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Sestrin2 prevents age-related intolerance to post myocardial infarction via AMPK/PGC-1α pathway

Published on Jan 1, 2018in Journal of Molecular and Cellular Cardiology5.055
· DOI :10.1016/j.yjmcc.2018.01.005
Nanhu Quan7
Estimated H-index: 7
(UMMC: University of Mississippi Medical Center),
Lin Wang6
Estimated H-index: 6
(UMMC: University of Mississippi Medical Center)
+ 5 AuthorsJi Li34
Estimated H-index: 34
(UMMC: University of Mississippi Medical Center)
Abstract
Abstract We have revealed that a novel stress-inducible protein, Sestrin2, declines in the heart with aging. Moreover, there is an interaction between Sestrin2 and energy sensor AMPK in the heart in response to ischemic stress. The objective of this study is to determine whether Sestrin2-AMPK complex modulates PGC-1α in the heart and protects the heart from ischemic insults. In order to characterize the role of cardiac Sestrin2-AMPK signaling cascade in aging, C57BL/6 wild type young mice (3–4 months), aged mice (24–26 months) and young Sestrin2 KO mice were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia. Intriguingly, ischemic AMPK activation was blunted in aged WT and young Sesn2 KO hearts as compared with young WT hearts. In addition, the AMPK downstream PGC-1α was down-regulated in the aged and Sestrin2 KO hearts during post myocardial infarction. To further determine the regulation of AMPK on mitochondrial functions in aging, the downstream of mitochondrial biogenesis PGC-1α transcriptional factor were measured. The results demonstrated that the PGC-1α downstream effectors TFAM and UCP2 were impaired in the aged and Sestrin2 KO post-MI hearts as compared to the young hearts. While the apoptotic flux markers such as AIF, Bax/Bcl-2 were up-regulated in both aged and Sestrin2 KO hearts versus young hearts. Furthermore, both Sestrin2 KO and aged hearts demonstrated more susceptible to ischemic insults as compared to young hearts. Additionally, the adeno-associated virus (AAV9)-Sestrin2 delivered to the aged hearts via a coronary delivery approach significantly rescued the ischemic tolerance of aged hearts. Taken together, the decreased Sestrin2 levels in aging lead to an impaired AMPK/PGC-1α signaling cascade and an increased sensitivity to ischemic insults.
  • References (32)
  • Citations (12)
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References32
Newest
#1Nanhu Quan (UMMC: University of Mississippi Medical Center)H-Index: 7
#2Wanqing Sun (UMMC: University of Mississippi Medical Center)H-Index: 5
Last. Ji Li (UMMC: University of Mississippi Medical Center)H-Index: 34
view all 10 authors...
24 CitationsSource
#1Hui Yang (UMMC: University of Mississippi Medical Center)H-Index: 3
#2Wanqing Sun (UMMC: University of Mississippi Medical Center)H-Index: 5
Last. Ji Li (UMMC: University of Mississippi Medical Center)H-Index: 34
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AMP-activated protein kinase (AMPK) signaling pathway plays a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. Notch1 signaling in the adult myocardium is also activated in response to ischemic stress. However, the relationship between Notch1 and AMPK signaling pathways during ischemia remains unclear. We hypothesize that Notch1 as an adaptive signaling pathway protects the heart from ischemic injury via modulating the cardioprotective AMPK signaling pathway....
19 CitationsSource
Background Four two-dimensional echocardiographic methods (cube, ellipsoid, Simpson's and area-length) can be used to assess left atrial volume (LAV). Aims To compare absolute LAV measurements and evaluate agreement regarding the semiquantitative assessment of degree of left atrial (LA) enlargement, between methods. Methods We prospectively measured LAV in 51 healthy volunteers using the four methods, and defined thresholds for moderate (mean + 2 standard deviations [SDs]) and severe (mean + 4 S...
3 CitationsSource
#1Hanseong Kim (UM: University of Michigan)H-Index: 6
#2Sojin An (UM: University of Michigan)H-Index: 4
Last. Uhn Soo Cho (UM: University of Michigan)H-Index: 14
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Sestrins are stress-inducible metabolic regulators with two seemingly unrelated but physiologically important functions: reduction of reactive oxygen species (ROS) and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). How Sestrins fulfil this dual role has remained elusive so far. Here we report the crystal structure of human Sestrin2 (hSesn2), and show that hSesn2 is twofold pseudo-symmetric with two globular subdomains, which are structurally similar but functionally distin...
43 CitationsSource
#1Yina Ma (UB: University at Buffalo)H-Index: 3
#2Ji Li (UB: University at Buffalo)H-Index: 34
The heart is a very special organ in the body and has a high requirement for metabolism due to its constant workload. As a consequence, to provide a consistent and sufficient energy a high steady-state demand of metabolism is required by the heart. When delicately balanced mechanisms are changed by physiological or pathophysiological conditions, the whole system’s homeostasis will be altered to a new balance, which contributes to the pathologic process. So it is no wonder that almost every heart...
23 CitationsSource
#1Alex Morrison (UB: University at Buffalo)H-Index: 8
#2Li Chen (JLU: Jilin University)H-Index: 3
Last. Ji Li (UB: University at Buffalo)H-Index: 34
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The regulation of AMPK in the ischemic heart remains incompletely understood. Recent evidence implicates the role of Sestrin2 in the AMPK signaling pathway, and it is hypothesized that Sestrin2 plays an influential role during myocardial ischemia to promote AMPK activation. Sestrin2 protein was found to be expressed in adult cardiomyocytes and accumulated in the heart during ischemic conditions. Sestrin2 knockout (KO) mice were used to determine the importance of Sestrin2 during ischemia and rep...
59 CitationsSource
#1Bo Lin ChenH-Index: 3
#2Meei Ling SheuH-Index: 18
Last. Shing-Hwa LiuH-Index: 39
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Abstract Aims: Renal ischemia-reperfusion (I/R) is a major cause of acute renal failure. The mechanisms of I/R injury include endoplasmic reticulum (ER) stress, inflammatory responses, hypoxia, and generation of reactive oxygen species (ROS). CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is involved in the ER stress signaling pathways. CHOP is a transcription factor and a major mediator of ER stress-induced apoptosis. However, the role of CHOP in renal I/R injury is still unde...
23 CitationsSource
#1Jingying WangH-Index: 7
#2Chao TongH-Index: 6
Last. Richard BucalaH-Index: 107
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Background—Macrophage migration inhibitory factor (MIF) exerts a protective effect on ischemic myocardium by activating AMP-activated protein kinase (AMPK). Small molecules that increase the affinity of MIF for its receptor have been recently designed, and we hypothesized that such agonists may enhance AMPK activation and limit ischemic tissue injury. Methods and Results—Treatment of cardiomyocytes with the candidate MIF agonist, MIF20, augmented AMPK phosphorylation, increased by 50% the surfac...
41 CitationsSource
#1Cheng-Wei XuH-Index: 1
#2Tian-Peng ZhangH-Index: 2
Last. Hui-Hua LiH-Index: 32
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Background: Carboxyl terminus of Hsp70-interacting protein (CHIP) is a chaperone/ubiquitin ligase that plays an important role in stress-induced apoptosis. Howeve
22 CitationsSource
#1Jun Hee Lee (UM: University of Michigan)H-Index: 30
#2Andrei V. Budanov (UCSD: University of California, San Diego)H-Index: 18
Last. Michael Karin (UCSD: University of California, San Diego)H-Index: 215
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Summary Chronic activation of mammalian target of rapamycin complex 1 (mTORC1) and p70 S6 kinase (S6K) in response to hypernutrition contributes to obesity-associated metabolic pathologies, including hepatosteatosis and insulin resistance. Sestrins are stress-inducible proteins that activate AMP-activated protein kinase (AMPK) and suppress mTORC1-S6K activity, but their role in mammalian physiology and metabolism has not been investigated. We show that Sestrin2—encoded by the Sesn2 locus, whose ...
117 CitationsSource
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#1Xiaolan Fan (Sichuan Agricultural University)H-Index: 5
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Abstract Sestrins (Sesns) represent a highly conserved family of stress-inducing proteins that are involved in antioxidant and autophagy regulatory functions. They are very important mediators as they can protect the cells under a variety of noxious stimulating conditions. However, the functions of Sesns in aging has not yet been fully understood. Here, we summarize the roles of Sesns in the aging process. A series of studies have shown that Sesns are highly involved in the aging process by regu...
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#1Di Ren (USF: University of South Florida)H-Index: 2
#2Nanhu Quan (UMMC: University of Mississippi Medical Center)
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Abstract Ischemia heart disease is the leading cause of death world-widely and has increased prevalence and exacerbated myocardial infarction with aging. Sestrin2, a stress-inducible protein, declines with aging in the heart and the rescue of Sestrin2 in the aged mouse heart improves the resistance to ischemic insults caused by ischemia and reperfusion. Here, through a combination of transcriptomic, physiological, histological, and biochemical strategies, we found that Sestrin2 deficiency shows ...
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Abnormal mitochondrial biogenesis and function has been linked to multiple diseases including diabetes. Recently, we demonstrated the role of renal (Pro)renin receptor (PRR) in the dysregulation of mitochondria. We hypothesized that PRR contributes to the reduction of mitochondrial biogenesis and function in diabetic kidney via PGC-1α/AMPK/SIRT-1 signaling pathway. In vivo and in vitro studies were conducted in C57BL/6 mouse and mouse renal mesangial cells (mRMCs). Control and streptozotocin-ind...
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