SESN2 protects against doxorubicin-induced cardiomyopathy via rescuing mitophagy and improving mitochondrial function

Wang, Panxia; Wang, Luping; Lü, Jing; Hu, Yuehuai; Wang, Qianqian; Li, Zhenzhen; Cai, Sidong; Liu, Liang; Guo, Kaiteng; Xie, Jiyan; Wang, Junjian; Lan, Rui; Shen, Juan

doi:10.1016/j.yjmcc.2019.06.005

Cited by 70 publications

(32 citation statements)

References 77 publications

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“…Sestrin2 was overexpressed by adenovirus or was knocked down by sgRNA in NRCMs. Consistent with our previous study (Wang et al, 2019), overexpression of SESN2 suppressed DOX-induced chromatin condensation and disorganized mitochondrial structure, and further decreased the protein level of cleaved caspase3 and BAX/Bcl2 ratio (Figures 7A-C). However, knockout SESN2 by targeting sgRNA obviously induced cardiomyocytes injury (Figures 7D-F).…”

Section: Involvement Of Sesn2 In Jmjd3-mediated Cardiotoxicity In Vitrosupporting

confidence: 92%

“…Subsequent experiments were performed to investigate the underlying mechanism between JMJD3 and SESN2 with chronic DOX stimulation. Inconsistent with our previous results that acute stimulation with DOX (1 µM, 12 h) had no effects on the transcription of SESN2 (Wang et al, 2019), DOX (0.5 µM, 48 h) chronically decreased the mRNA level of SESN2 ( Figure 2K). Therefore, proteasome inhibitor MG132 (10 µM) was co-treated with DOX at 1 µM for 12 h or DOX at 0.5 µM for 48 h to cardiomyocytes and the protein level of SESN2 was measured.…”

Section: Jmjd3 Decreased H3k27me3 Enrichment In the Promoter Region Osupporting

confidence: 91%

“…Oligos corresponding to the sgRNAs were synthesized and cloned into lenti-CRISPR v2 vectors (Addgene, plasmid #52961). According to our previous study, lentiCRISPRv2-gRNA or lentiCRISPRv2, psPAX2 and pMD2.G were simultaneously co-transfected into HEK293T cell for 48 h to generate lentivirus (Wang et al, 2019). NRCMs were plated into 35 mm dishes and one milliliter of virus suspension was added into the culture medium.…”

Section: Chromatin Immunoprecipitation (Chip)-qpcr Analysismentioning

confidence: 99%

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Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression

Wang

Lan

Guo

et al. 2020

Front. Cell Dev. Biol.

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Jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, specifically catalyzes the demethylation of H3K27 (H3K27me3) and regulates gene expression. Sestrin2 (SESN2), a stress-inducible protein, protected against doxorubicin (DOX)-induced cardiomyopathy by regulating mitophagy and mitochondrial function. Here, the expression of JMJD3 was increased and that of SESN2 was decreased in both the heart samples from patients with dilated cardiomyopathy and chronic DOXstimulation induced cardiomyopathy. Inhibition or knockdown of JMJD3 attenuated DOX-induced cardiomyocytes apoptosis, mitochondrial injury and cardiac dysfunction. However, JMJD3 overexpression aggravated DOX-induced cardiomyopathy, which were relieved by SESN2 overexpression. JMJD3 inhibited the transcription of SESN2 by reducing tri-methylation of H3K27 in the promoter region of SESN2. In conclusion, JMJD3 negatively regulated SESN2 via decreasing H3K27me3 enrichment in the promoter region of SESN2, subsequently inducing mitochondrial dysfunction and cardiomyocytes apoptosis. Targeting the JMJD3-SESN2 signaling axis may be a potential therapeutic strategy to protect against DOX-mediated cardiomyopathy.

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Section: Involvement Of Sesn2 In Jmjd3-mediated Cardiotoxicity In Vitrosupporting

confidence: 92%

Section: Jmjd3 Decreased H3k27me3 Enrichment In the Promoter Region Osupporting

confidence: 91%

Section: Chromatin Immunoprecipitation (Chip)-qpcr Analysismentioning

confidence: 99%

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Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression

Wang

Lan

Guo

et al. 2020

Front. Cell Dev. Biol.

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“…Foxo1 and its downstream targets play a key role in mitochondrial biogenesis [39]. Transient insulin stimulation activates the PI3K-AKT signaling pathway and suppresses Foxo1 activation.…”

Section: Discussionmentioning

confidence: 99%

Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

Wang

Bai

Duan³

et al. 2020

Preprint

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Background: Diabetic cardiomyopathy (DCM) severely impairs the health of diabetic patients. Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 DCM have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM.Methods: The cardiac function in mice was analyzed by echocardiography, ELISA, hematoxylin and eosin staining, TUNEL and transmission electron microscopy. The mitochondrial function in cardiomyocytes was measured by the oxygen consumption rate and the mitochondrial membrane potential (ΔΨm). Kir6.1 expression at the mRNA and protein levels was analyzed by quantitative real-time PCR and western blotting (WB), respectively. The protein expression of t-AKT, p-AKT, t-Foxo1, and p-Foxo1 was analyzed by WB.Results: We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. Kir6.1 overexpression improved cardiac dysfunction and upregulated the phosphorylation of AKT and Foxo1 in the DCM mouse model. Furthermore, Kir6.1 overexpression also improved cardiomyocyte dysfunction and upregulated the phosphorylation of AKT and Foxo1 in cardiomyocytes with insulin resistance. In contrast, cardiac-specific Kir6.1 knockout aggravated the cardiac dysfunction and downregulated the phosphorylation of AKT and Foxo1 in DCM mice. Furthermore, Foxo1 activation downregulated the expression of Kir6.1 and decreased the ΔΨm in cardiomyocytes. In contrast, Foxo1 inactivation upregulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional Foxo1-binding site .Conclusions: Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-Foxo1 signaling pathway. Moreover, the crosstalk between Kir6.1 and the AKT-Foxo1 signaling pathway may provide new strategies for reversing the defective signaling in DCM.

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“…Mitochondrial autophagy is a conserved cellular process to degrade and recycle damaged mitochondria through formation of autophagosomes and fusion with lysosomes. Autophagy has been shown to play a rather complex role in doxorubicin-induced cardiotoxicity due to excessive or defective autophagy (Li et al, 2016;Koleini and Kardami, 2017;Wang et al, 2019a). It appears that the onset and development of doxorubicin-induced cardiotoxicity is dependent upon drug dosage and duration (Wenningmann et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Luteolin Attenuates Doxorubicin-Induced Cardiotoxicity Through Promoting Mitochondrial Autophagy

Sun

et al. 2020

Front. Physiol.

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Doxorubicin is a valuable antineoplastic drug although its clinical use is greatly hindered by its severe cardiotoxicity with dismal target therapy available. Luteolin is a natural product extracted from vegetables and fruits with a wide range of biological efficacies including anti-oxidative, anti-tumorigenic, and anti-inflammatory properties. This study was designed to examine the possible effect of luteolin on doxorubicin-induced cardiotoxicity, if any, and the mechanism(s) involved with a focus on mitochondrial autophagy. Luteolin application (10 µM) in adult mouse cardiomyocytes overtly improved doxorubicin-induced cardiomyocyte contractile dysfunction including elevated peak shortening amplitude and maximal velocity of shortening/relengthening along with unchanged duration of shortening and relengthening. Luteolin alleviated doxorubicininduced cardiotoxicity including apoptosis, accumulation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Furthermore, luteolin attenuated doxorubicin-induced cardiotoxicity through promoting mitochondrial autophagy in association with facilitating phosphorylation of Drp1 at Ser 616 , and upregulating TFEB expression. In addition, luteolin treatment partially attenuated low dose doxorubicininduced elongation of mitochondria. Treatment of Mdivi-1, a Drp1 GTPase inhibitor, negated the protective effect of luteolin on levels of TFEB, LAMP1, and LC3B, as well as loss of mitochondrial membrane potential and cardiomyocyte contractile dysfunction in the face of doxorubicin challenge. Taken together, these findings provide novel insights for the therapeutic efficacy of luteolin against doxorubicin-induced cardiotoxicity possibly through improved mitochondrial autophagy.

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SESN2 protects against doxorubicin-induced cardiomyopathy via rescuing mitophagy and improving mitochondrial function

Cited by 70 publications

References 77 publications

Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression

Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression

Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

Luteolin Attenuates Doxorubicin-Induced Cardiotoxicity Through Promoting Mitochondrial Autophagy

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