miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice

Hu, Xiaoping; Liu, Huagang; Wang, Zhiwei; Hu, Zhipeng; Li, Luocheng

doi:10.1155/2019/1512326

Cited by 51 publications

(43 citation statements)

References 33 publications

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“…Previous studies provided a robust evidence to support a cross-talk between Nrf2 and miR-200a [ 20 , 21 ]. Hence, we speculated that miR-200a could act as an upstream of Nrf2, and was closely involved in the effect of PIC in macrophages.…”

Section: Resultsmentioning

confidence: 99%

Piceatannol inhibits pyroptosis and suppresses oxLDL-induced lipid storage in macrophages by regulating miR-200a/Nrf2/GSDMD axis

Zhang

Peng

2020

Bioscience Reports

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As a major bioactive compound from grapes, piceatannol has been reported to exert anti-atherosclerotic activity in various studies. Nevertheless, the mechanism underlying the effect of piceatannol against atherosclerosis is elusive. Our study identified miR-200a/Nrf2/GSDMD signaling pathway as critical mediators in the effect of piceatannol on macrophages. In this study, we confirmed that treatment of piceatannol repressed the oxLDL-induced lipid storage in macrophages. Compared to control group, piceatannol inhibited TG storage and the activity of caspase1. It is noting that in response to oxLDL challenge, piceatannol abated the pyroptosis in RAW264.7 cells, with a decreased expression of caspase1, GSDMD, IL-18, IL-1b and NLRP3. Moreover, we investigated the role of miR-200a/Nrf2 signaling pathway in the effect of piceatannol. The results declared that after transfection of si-miR-200a or si-Nrf2 plasmids, the effects of piceatannol on macrophages were converted, including lipid storage and pyroptosis. Importantly, si-miR-200a plasmid reduced the expression of Nrf2, indicating that miR-200a acted as an enhancer of Nrf2 in macrophages. Collectively, our findings demonstrate that piceatannol exerts anti-atherosclerotic activity on RAW264.7 cells by regulating miR-200a/Nrf2/GSDMD signaling. This study is the first time to identify miR-200a as a candidate target in atherosclerosis and declared an association between miR-200a and pyroptosis, which provides a novel therapy for the treatment of atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Piceatannol inhibits pyroptosis and suppresses oxLDL-induced lipid storage in macrophages by regulating miR-200a/Nrf2/GSDMD axis

Zhang

Peng

2020

Bioscience Reports

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“…Furthermore, miRNA-200a inhibits apoptosis and inflammation in cardiomyocytes by regulating Keap1/Nrf2 signaling in favor of cell protection [142]. In mice exposed to DOX, miRNA-200a enhances Nrf2 expression to improve contractile function, and prevent apoptosis and oxidative stress [143].…”

Section: Nrf2 Modulationmentioning

confidence: 99%

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

et al. 2021

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Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

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“…miRNAs have been reported to regulate the activation of the Keap1-Nrf2 pathway [ 14 , 15 ]. miR-200a could target Keap1 mRNA and promote degradation of Keap1, resulting in Nrf2 activation to protect against DOX-induced cardiotoxicity in mice [ 16 ]. The miR-152 family has been implicated in processes of immunomodulation, cell growth, and proliferation [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Zhang

Lai

Guo

2021

Oxidative Medicine and Cellular Longevity

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Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.

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miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice

Cited by 51 publications

References 33 publications

Piceatannol inhibits pyroptosis and suppresses oxLDL-induced lipid storage in macrophages by regulating miR-200a/Nrf2/GSDMD axis

Piceatannol inhibits pyroptosis and suppresses oxLDL-induced lipid storage in macrophages by regulating miR-200a/Nrf2/GSDMD axis

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

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