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

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.

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

“…We found that Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. These findings further confirm that Sesn2 is a potential target that could prevent age-related susceptibility to ischemic heart disease [105,106].…”

Sestrin‑2 regulates podocyte mitochondrial dysfunction�and apoptosis under high‑glucose conditions via AMPK

“…As a stress-inducible metabolic regulator, sesn2 has been proven to protect the mitochondria from oxidative damage both in vivo and in vitro (32,33). To clarify the potential association between sesn2 and AMPK, the expression of these two molecules was determined in diabetic rats ( Fig.…”

Sodium Houttuyfonate Alleviates Post-infarct Remodeling in Rats via AMP-Activated Protein Kinase Pathway

“…et al, 2017 ). On the other hand, AMPK has been widely known involved in coordinating a series pathophysiological responses under ischemic stress, and pharmacological activation of AMPK has been found preventing inflammation and cellular death, reducing cardiac remodeling post-myocardial infarction ( Calvert et al, 2008 ; Peairs et al, 2009 ; Chiang et al, 2017 ; Kim et al, 2017 ; Quan et al, 2018 ). In our study, we found that SH treatment elevated the activation of AMPK on post-infarct heart and post-hypoxia H9C2.…”

“…Adenosine monophosphate-activated protein kinase (AMPK), which consisted of three subunits, α, β, γ, that together made a functional enzyme, worked as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions, such as ischemia and nutritional stress ( Calvert et al, 2008 ; Quan et al, 2018 ). Activation of AMPK has been confirmed exerting pleiotropic functions against inflammatory response and tissue fibrosis and owning beneficial properties in a series of diseases ( Peairs et al, 2009 ; Chiang et al, 2017 ; Kim et al, 2017 ).…”