SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway

He, Ling; Wang, Jihong; Yang, Yuting; Zou, Pengtao; Xia, Zirong; Li, Juxiang

doi:10.1016/j.tox.2022.153119

Cited by 29 publications

(13 citation statements)

References 34 publications

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“…[42,43] In a cohort of more than 2000 patients treated with doxorubicin chemotherapy, a follow-up study found that 9% of patients showed cardiotoxicity with a decrease in LVEF of 10% −50%. [44,45] Our results found that DOX exposure caused the decrease of EF and SV in rats, which is in accordance with previous reports in mice, [46] whereas VitB 6 supplement could increase EF and SV. BNP is another indicator to evaluate cardiac function, which will be released into the blood in large quantities [47,48] when the heart was injured by DOX.…”

Section: F I G U R E 4 (See Caption On Next Page)supporting

confidence: 92%

Protective effect of vitamin B₆ against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

Sun,

Wang,

Gui

et al. 2023

J Biochem & Molecular Tox

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Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+/H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX‐induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX‐induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl‐2‐associated X protein/B‐cell lymphoma‐2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX‐induced cardiotoxicity.

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Section: F I G U R E 4 (See Caption On Next Page)supporting

confidence: 92%

Protective effect of vitamin B₆ against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

Sun,

Wang,

Gui

et al. 2023

J Biochem & Molecular Tox

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“… 307 Overexpression of SIRT4 inhibits ROS production and autophagy by activating the Akt/mTOR signaling pathway. 308 Furthermore, the SIRT4/optic atrophy 1 axis is causally linked to mitochondrial dysfunction and altered mitochondrial dynamics that translates into aging-associated decreased mitophagy. 301 So far, there are few relevant studies on SIRT4 regulation of autophagy.…”

Section: Introductionmentioning

confidence: 99%

The sirtuin family in health and disease

Zhang

Chen

et al. 2022

Sig Transduct Target Ther

229

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Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

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“…Wang et al found thatSIRT4 overexpression in hepatocellular carcinomas could activate autophagy by inhibiting glutamine metabolism and increasing ADP/AMP levels, thereby activating the LKB1/AMPKα/mTOR signaling pathway [ 16 ]. In the cardiovascular system, SIRT4 overexpression has been reported to protect cardiomyocytes from doxorubicin-induced cardiotoxicity by inhibiting Akt/mTOR-dependent autophagy [ 53 ]. In the pancreas, SIRT4 can deactivate autophagic function by deregulating AMPK and directly inhibiting insulin secretion [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Autophagy in Rat Müller Glial Cells Is Modulated by the Sirtuin 4/AMPK/mTOR Pathway and Induces Apoptosis under Oxidative Stress

Qin

Xie

Cao

et al. 2022

Cells

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Müller glial cells (MGCs) are a group of glial cells in the retina that provide essential support to retinal neurons; however, the understanding of MGC apoptosis and autophagy remains limited. This study was aimed at investigating the role of autophagy in MGCs under normal and oxidative conditions, and identifying the underlying mechanisms. In addition, the sirtuin 4 (SIRT4)-mediated signaling pathway was observed to regulate the autophagic process in MGCs. To assess the effect of autophagy on MGC mitochondrial function and survival, we treated rMC-1 cells—rat-derived Müller glial cells—with rapamycin and 3-methyladenine (3-MA), and found that MGC death was not induced by such treatment, while autophagic dysfunction could increase MGC apoptosis under oxidative stress, as reflected by the expression level of cleaved caspase 3 and PI staining. In addition, the downregulation of autophagy by 3-MA could influence the morphology of the mitochondrial network structure, the mitochondrial membrane potential, and generation of reactive oxygen species (ROS) under oxidative stress. Moreover, SIRT4 depletion enhanced autophagosome formation, as verified by an increase in the LC3 II/I ratio and a decrease in the expression of SQSTM1/p62, and vice versa. The inhibition of AMPK phosphorylation by compound C could reverse these changes in LC3 II/I and SQSTM1/p62 caused by SIRT4 knockdown. Our research concludes that MGCs can endure autophagic dysfunction in the absence of oxidative stress, while the downregulation of autophagy can cause MGCs to become more sensitized to oxidative stress. Simultaneous exposure to oxidative stress and autophagic dysfunction in MGCs can result in a pronounced impairment of cell survival. Mechanically, SIRT4 depletion can activate the autophagic process in MGCs by regulating the AMPK–mTOR signaling pathway.

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SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway

Cited by 29 publications

References 34 publications

Protective effect of vitamin B₆ against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

Protective effect of vitamin B₆ against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

The sirtuin family in health and disease

Autophagy in Rat Müller Glial Cells Is Modulated by the Sirtuin 4/AMPK/mTOR Pathway and Induces Apoptosis under Oxidative Stress

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SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway

Cited by 29 publications

References 34 publications

Protective effect of vitamin B6 against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

Protective effect of vitamin B6 against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

The sirtuin family in health and disease

Autophagy in Rat Müller Glial Cells Is Modulated by the Sirtuin 4/AMPK/mTOR Pathway and Induces Apoptosis under Oxidative Stress

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Protective effect of vitamin B₆ against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression

Protective effect of vitamin B₆ against doxorubicin‐induced cardiotoxicity by modulating NHE1 expression