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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 Cardiology5.05
· DOI :10.1016/j.yjmcc.2018.01.005
Nanhu Quan5
Estimated H-index: 5
(UMMC: University of Mississippi Medical Center),
Lin Wang5
Estimated H-index: 5
(UMMC: University of Mississippi Medical Center)
+ 5 AuthorsJi Li6
Estimated H-index: 6
(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 (9)
References32
Newest
#1Nanhu Quan (UMMC: University of Mississippi Medical Center)H-Index: 5
#2Wanqing Sun (UMMC: University of Mississippi Medical Center)H-Index: 5
Last.Ji Li (UMMC: University of Mississippi Medical Center)H-Index: 6
view all 10 authors...
#1Hui Yang (UMMC: University of Mississippi Medical Center)H-Index: 2
#2Wanqing Sun (UMMC: University of Mississippi Medical Center)H-Index: 5
Last.Ji Li (UMMC: University of Mississippi Medical Center)H-Index: 6
view all 9 authors...
#1Yina Ma (UB: University at Buffalo)H-Index: 1
#2Ji Li (UB: University at Buffalo)H-Index: 1
#1Alex Morrison (UB: University at Buffalo)H-Index: 8
#2Li Chen (JLU: Jilin University)H-Index: 1
Last.Ji Li (UB: University at Buffalo)H-Index: 11
view all 10 authors...
#1Jun Hee Lee (UM: University of Michigan)H-Index: 30
#2Andrei V. Budanov (UCSD: University of California, San Diego)H-Index: 17
Last.Insook Jang (UM: University of Michigan)H-Index: 6
view all 19 authors...
Cited By9
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#1Panxia Wang (SYSU: Sun Yat-sen University)H-Index: 3
#2Luping Wang (SCUT: South China University of Technology)H-Index: 2
Last.Jiyan Xie (Memorial Hospital of South Bend)
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#1David J. Papadopoli (McGill University)H-Index: 3
#2Karine Boulay (UdeM: Université de Montréal)H-Index: 4
Last.Laura Hulea (UdeM: Université de Montréal)
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#1Ruiting Li (CPU: China Pharmaceutical University)H-Index: 1
#2Ruiting Li (UM: University of Michigan)
Last.Jun Hee Lee (UM: University of Michigan)H-Index: 30
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#1Ahmed A. Mohsin (VCU: Virginia Commonwealth University)H-Index: 1
#2Qun Chen (VCU: Virginia Commonwealth University)H-Index: 31
Last.Edward J. Lesnefsky (VCU: Virginia Commonwealth University)H-Index: 17
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#1Jinda Huang (Southern Medical University)H-Index: 3
#2Wanwan Peng (Southern Medical University)H-Index: 1
Last.Qiyi Zeng (Southern Medical University)H-Index: 2
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#1Dong Liu (Peking Union Medical College)H-Index: 3
#2Zhiqiang Ma (Fourth Military Medical University)H-Index: 15
Last.Jiansong Yuan (Peking Union Medical College)H-Index: 1
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#1Chunhu Gu (Fourth Military Medical University)H-Index: 2
#2Tian Li (Fourth Military Medical University)H-Index: 12
Last.Minfeng Fang (MOE: Chinese Ministry of Education)H-Index: 1
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#1Cheng Zheng (WMU: Wenzhou Medical College)H-Index: 1
#2Jia‐Feng Lin (WMU: Wenzhou Medical College)H-Index: 4
Last.Xiao-Wei Li (WMU: Wenzhou Medical College)
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