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Publication
Cardioprotective roles of sestrin 1 and sestrin 2 against doxorubicin
cardiotoxicity.
Authors Li R, Huang Y, Semple I, Kim M, Zhang Z, Lee JH
Submitted By Submitted Externally on 3/26/2020
Status Published
Journal American journal of physiology. Heart and circulatory physiology
Year 2019
Date Published 7/1/2019
Volume : Pages 317 : H39 - H48
PubMed Reference 31026186
Abstract Doxorubicin is a chemotherapy medication widely used to treat a variety of
cancers. Even though it offers one of the most effective anti-cancer treatments,
its clinical use is limited because of its strong cardiotoxicity that can lead
to fatal conditions. Here, we show that sestrin 1 and sestrin 2, members of the
sestrin family of proteins that are stress-inducible regulators of metabolism,
are critical for suppressing doxorubicin cardiotoxicity and coordinating the
AMPK-mammalian target of rapamycin complex 1 (mTORC1) autophagy signaling
network for cardioprotection. Expression of both sestrin 1 and sestrin 2 was
highly increased in the mouse heart after doxorubicin injection. Genetic
ablation of sestrin 1 and sestrin 2 rendered mice more vulnerable to doxorubicin
and exacerbated doxorubicin-induced cardiac pathologies including cardiomyocyte
apoptosis and cardiac dysfunction. These pathologies were associated with strong
dysregulation of the cardiac signaling network, including suppression of the
AMPK pathway and activation of the mTORC1 pathway. Consistent with AMPK
downregulation and mTORC1 upregulation, autophagic activity of heart tissue was
diminished, leading to prominent accumulation of autophagy substrate,
p62/SQSTM1. Taken together, our results indicate that sestrin 1 and sestrin 2
are important cardioprotective proteins that coordinate metabolic signaling
pathways and autophagy to minimize cardiac damage in response to doxorubicin
insult. Augmenting this protective mechanism could provide a novel therapeutic
rationale for prevention and treatment of doxorubicin cardiotoxicity. NEW &
NOTEWORTHY Doxorubicin is a highly efficient chemotherapeutic medicine; however,
its use is limited because of its strong cardiotoxicity. Here, we show that
sestrin 1 and sestrin 2 are critical protectors of cardiomyocytes from
doxorubicin damage. By upregulating AMPK and autophagic activities and
suppressing mammalian target of rapamycin complex 1 and oxidative stress,
sestrins counteract detrimental effects of doxorubicin on cardiomyocytes.
Correspondingly, loss of sestrin 1 and sestrin 2 produced remarkable
dysregulation of these pathways, leading to prominent cardiac cell death and
deterioration of heart function.




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