SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation

Zhang, Yanping; Ni, Le; Lin, Bo; Hu, Lingjie; Lin, Zheyi; Yang, Jian; Wang, Jinyu; Ma, Honghui; Liu, Yi; Lin, Jianghua; Xu, Liang; Wu, Liqun; Shi, Dan

doi:10.1016/j.phrs.2021.105642

Cited by 8 publications

(6 citation statements)

References 62 publications

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“…DOX-induced cardiotoxicity is a classical chronic cardiotoxic model [ 2 , 3 ]. The mice received a low dose of DOX (5 mg/kg/week) intraperitoneally for 5 weeks.…”

Section: Resultsmentioning

confidence: 99%

“…However, the significant adverse effects of DOX, particularly on the heart, pose substantial challenges to the health of cancer patients and survivors, limiting its clinical application [ 2 ]. Cardiotoxicity induced by DOX is well-established, showing both cumulative-dose-dependent acute and chronic forms, including aberrant arrhythmias, ventricular dysfunction, and heart failure [ 3 ]. Despite progress in understanding cellular pathways affected by anthracyclines, pinpointing the precise molecular origins of acute or late-stage cardiotoxicity remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity

Zhu,

Lian,

Wang

et al. 2024

Chin Med

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Background Liguzinediol (Lig) has emerged as a promising candidate for mitigating Doxorubicin (DOX)-induced cardiotoxicity, a significant limitation in the clinical application of this widely used antineoplastic drug known for its efficacy. This study aimed to explore the effects and potential mechanisms underlying Lig’s protective role against DOX-induced cardiotoxicity. Methods C57BL/6 mice were treated with DOX. Cardiac function changes were observed by echocardiography. Cardiac structure changes were observed by HE and Masson staining. Immunofluorescence was applied to visualize the cardiomyocyte apoptosis. Western blotting was used to detect the expression levels of AMP-activated protein kinase (AMPK), sirtuin 3 (SIRT3), Caspase-3 and gasdermin E N-terminal fragment (GSDME-N). These experiments confirmed that Lig had an ameliorative effect on DOX-induced cardiotoxicity in mice. Results The results demonstrated that Lig effectively countered myocardial oxidative stress by modulating intracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Lig reduced levels of creatine kinase (CK) and lactate dehydrogenase (LDH), while ameliorating histopathological changes and improving electrocardiogram profiles in vivo. Furthermore, the study revealed that Lig activated the AMPK/SIRT3 pathway, thereby enhancing mitochondrial function and attenuating myocardial cell apoptosis. In experiments with H9C2 cells treated with DOX, co-administration of the AMPK inhibitor compound C (CC) led to a significant increase in intracellular ROS levels. Lig intervention reversed these effects, along with the downregulation of GSDME-N, interleukin-1β (IL-1β), and interleukin-6 (IL-6), suggesting a potential role of Lig in mitigating Caspase-3/GSDME-mediated pyroptosis. Conclusion The findings of this study suggest that Lig effectively alleviates DOX-induced cardiotoxicity through the activation of the AMPK/SIRT3 pathway, thereby presenting itself as a natural product with therapeutic potential for preventing DOX-associated cardiotoxicity. This novel approach may pave the way for the development of alternative strategies in the clinical management of DOX-induced cardiac complications.

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“…DOX-induced cardiotoxicity is a classical chronic cardiotoxic model [ 2 , 3 ]. The mice received a low dose of DOX (5 mg/kg/week) intraperitoneally for 5 weeks.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity

Zhu,

Lian,

Wang

et al. 2024

Chin Med

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show abstract

“…RNA purification and qRT-PCR were performed as described in our previous study [ 58 ]. Briefly, total RNA purification from neonatal and adult cardiomyocytes or heart tissue was conducted with RNAiso plus reagent (Takara, 9109) based on the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis

Lin

Shen

et al. 2022

Cell Death Discov.

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Sepsis is a life-threatening syndrome with multi-organ dysfunction in critical care medicine. With the occurrence of sepsis-induced cardiomyopathy (SIC), characterized by reduced ventricular contractility, the mortality of sepsis is boosted to 70–90%. Pyruvate kinase M2 (PKM2) functions in a variety of biological processes and diseases other than glycolysis, and has been documented as a cardioprotective factor in several heart diseases. It is currently unknown whether PKM2 influences the development of SIC. Here, we found that PKM2 was upregulated in cardiomyocytes treated with LPS both in vitro and in vivo. Pkm2 inhibition exacerbated the LPS-induced cardiac damage to neonatal rat cardiomyocytes (NRCMs). Furthermore, cardiomyocytes lacking PKM2 aggravated LPS-induced cardiomyopathy, including myocardial damage and impaired contractility, whereas PKM2 overexpression and activation mitigated SIC. Mechanism investigation revealed that PKM2 interacted with sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), a key regulator of the excitation-contraction coupling, to maintain calcium homeostasis, and PKM2 deficiency exacerbated LPS-induced cardiac systolic dysfunction by impairing SERCA2a expression. In conclusion, these findings highlight that PKM2 plays an essential role in gram-negative sepsis-induced cardiomyopathy, which provides an attractive target for the prevention and treatment of septic cardiomyopathy.

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“…et al reported another promising therapeutic target for DIC, namely tumor-suppressive human circular RNA CircITCH [ 37 ]. Other recent potential strategies that possibly reverse DIC include atg7 -based autophagy activation [ 38 ], meteorin-like (METRNL) protein [ 39 ], sirtuin 1 (SIRT1) [ 40 ], berberine [ 41 ], ADAR2 [ 42 ], elabela (ELA) [ 43 ], phenylalanine-butyramide (FBA) [ 44 ], gasdermin D [ 45 ], melatonin [ 46 ], levosimendan [ 47 ], paeonol [ 48 ], SNX17 [ 49 ], irisin [ 50 ], isorhapontigenin [ 51 ], liensinine [ 52 ], etc.…”

Section: Severe Neuropathy and Myopathy Side Effects In Chemotherapymentioning

confidence: 99%

The Battlefield of Chemotherapy in Pediatric Cancers

Wang

et al. 2023

Cancers

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The survival rate for pediatric cancers has remarkably improved in recent years. Conventional chemotherapy plays a crucial role in treating pediatric cancers, especially in low- and middle-income countries where access to advanced treatments may be limited. The Food and Drug Administration (FDA) approved chemotherapy drugs that can be used in children have expanded, but patients still face numerous side effects from the treatment. In addition, multidrug resistance (MDR) continues to pose a major challenge in improving the survival rates for a significant number of patients. This review focuses on the severe side effects of pediatric chemotherapy, including doxorubicin-induced cardiotoxicity (DIC) and vincristine-induced peripheral neuropathy (VIPN). We also delve into the mechanisms of MDR in chemotherapy to the improve survival and reduce the toxicity of treatment. Additionally, the review focuses on various drug transporters found in common types of pediatric tumors, which could offer different therapeutic options.

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SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation

Cited by 8 publications

References 62 publications

Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity

Liguzinediol potentiates the metabolic remodeling by activating the AMPK/SIRT3 pathway and represses Caspase-3/GSDME-mediated pyroptosis to ameliorate cardiotoxicity

PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis

The Battlefield of Chemotherapy in Pediatric Cancers

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