Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage

Deng, Shan; Essandoh, Kobina; Wang, Xiaohong; Li, Yutian; Huang, Wei; Chen, Jing; Peng, Jiangtong; Jiang, Ding‐Sheng; Mu, Xingjiang; Wang, Chenran; Peng, Tianqing; Guan, Jun‐Lin; Wang, Yigang; Jegga, Anil G.; Huang, Kai; Fan, Guo-Chang

doi:10.1016/j.redox.2020.101453

Cited by 41 publications

(36 citation statements)

References 47 publications

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“…To investigate the possible role of Tsg101 in Glut-4 translocation during ischemia, we generated a mouse model with heart-specific overexpression of Tsg101. Such transgenic (TG) mice have been phenotypically characterized in our previous publications [ 24 , 25 , 26 ] and validated here that Tsg101 was overexpressed by ~4-fold in TG hearts, compared to WT-hearts ( Figure 2 A,B). Interestingly, total levels of Glut-4 were also significantly higher in TG hearts than WT hearts ( Figure 2 A,C).…”

Section: Resultssupporting

confidence: 79%

“…While ischemic hearts are insulin-resistant and rely on endosomal recycling of Glut-4, a more in-depth investigation is still needed to ascertain the role of Tsg101 in Glut-4 translocation in the presence or absence of insulin stimulation. Second, our recent work reported that Tsg101 protein levels were downregulated in I/R hearts after 45-min ex vivo no-flow ischemia and 1-h reperfusion [ 25 ]. In the present study, we observed that Tsg101 levels were upregulated after 45-min ischemia, suggesting an initial increase of Tsg101 protein levels in the ischemic phase and a decrease in the reperfusion phase.…”

Section: Discussionmentioning

confidence: 99%

“…The Langendorff perfusion apparatus was used for the ex vivo model of ischemia/reperfusion in mouse hearts as described previously with few modifications [ 25 ]. In brief, mice were anesthetized, and hearts were excised and promptly cannulated and mounted to the Langendorff retrograde heart perfusion system.…”

Section: Methodsmentioning

confidence: 99%

“…Most recently, our lab observed that Tsg101 promoted the endosomal-mediated transport of the insulin-like growth factor-1 receptor (IGF-1R) to the plasma membrane (sarcolemma) of cardiomyocytes, leading to physiological cardiac hypertrophy [ 24 ]. Furthermore, we observed that overexpression of Tsg101 in the heart protected against I/R-induced cardiac injury [ 25 ]. Hence, these novel findings prompted us to test whether Tsg101 could positively regulate sarcolemma Glut-4 levels in I/R hearts through endosomal-mediated recycling.…”

Section: Introductionmentioning

confidence: 99%

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Tsg101 Is Involved in the Sorting and Re-Distribution of Glucose Transporter-4 to the Sarcolemma Membrane of Cardiac Myocytes

Essandoh

Deng

Wang

et al. 2020

Cells

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Cardiac cells can adapt to pathological stress-induced energy crisis by shifting from fatty acid oxidation to glycolysis. However, the use of glucose-insulin-potassium (GIK) solution in patients undergoing cardiac surgery does not alleviate ischemia/reperfusion (I/R)-induced energy shortage. This indicates that insulin-mediated translocation of glucose transporter-4 (Glut-4) is impaired in ischemic hearts. Indeed, cardiac myocytes contain two intracellular populations of Glut-4: an insulin-dependent non-endosomal pool (also referred to as Glut-4 storage vesicles, GSVs) and an insulin-independent endosomal pool. Tumor susceptibility gene 101 (Tsg101) has been implicated in the endosomal recycling of membrane proteins. In this study, we aimed to examine whether Tsg101 regulated the sorting and re-distribution of Glut-4 to the sarcolemma membrane of cardiomyocytes under basal and ischemic conditions, using gain- and loss-of-function approaches. Forced overexpression of Tsg101 in mouse hearts and isolated cardiomyocytes could promote Glut-4 re-distribution to the sarcolemma, leading to enhanced glucose entry and adenosine triphosphate (ATP) generation in I/R hearts which in turn, attenuation of I/R-induced cardiac dysfunction. Conversely, knockdown of Tsg101 in cardiac myocytes exhibited opposite effects. Mechanistically, we identified that Tsg101 could interact and co-localize with Glut-4 in the sarcolemma membrane of cardiomyocytes. Our findings define Tsg101 as a novel regulator of cardiac Glut-4 trafficking, which may provide a new therapeutic strategy for the treatment of ischemic heart disease.

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tsg101 Is Involved in the Sorting and Re-Distribution of Glucose Transporter-4 to the Sarcolemma Membrane of Cardiac Myocytes

Essandoh

Deng

Wang

et al. 2020

Cells

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“…compared to C57BL/6J mice (∼0.5-fold increases in autophagic flux by 6 h of chloroquine at a dose of 50 mg/kg, i.p. ; Fernandez et al, 2018 ; Deng et al, 2020 ). Thus, a plausible explanation is that CR-Nrf2 Tg overexpression-induced cardiac protection is mostly likely due to an intact state of myocardial autophagy by 4 weeks after TAC in FVB/N mice.…”

Section: Nrf2-mediated Cardiac Damagementioning

confidence: 99%

The Dark Side of Nrf2 in the Heart

2020

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Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) is a critical transcription factor that regulates the expression of over 1000 genes in the cell under normal and stressed conditions. These transcripts can be categorized into different groups with distinct functions, including antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic degradation, and metabolism. Nevertheless, Nrf2 has been historically considered as a crucial regulator of antioxidant defense to protect against various insult-induced organ damage and has evolved as a promising drug target for the treatment of human diseases, such as heart failure. However, burgeoning evidence has revealed a detrimental role of Nrf2 in cardiac pathological remodeling and dysfunction toward heart failure. In this mini-review, we outline recent advances in structural features of Nrf2 and regulation of Nrf2 activity and discuss the emerging dark side of Nrf2 in the heart as well as the potential mechanisms of Nrf2-mediated myocardial damage and dysfunction.

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Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies

Sun,

Liu,

Liang

et al. 2024

Phytotherapy Research

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Diosmetin, a natural occurring flavonoid, is primarily found in citrus fruits, beans, and other plants. Diosmetin demonstrates a variety of pharmacological activities, including anticancer, antioxidant, anti‐inflammatory, antibacterial, metabolic regulation, cardiovascular function improvement, estrogenic effects, and others. The process of literature search was done using PubMed, Web of Science and ClinicalTrials databases with search terms containing Diosmetin, content, anticancer, anti‐inflammatory, antioxidant, pharmacological activity, pharmacokinetics, in vivo, and in vitro. The aim of this review is to summarize the in vivo, in vitro and clinical studies of Diosmetin over the last decade, focusing on studies related to its anticancer, anti‐inflammatory, and antioxidant activities. It is found that DIO has significant therapeutic effects on skin and cardiovascular system diseases, and its research in pharmacokinetics and toxicology is summarized. It provides the latest information for researchers and points out the limitations of current research and areas that should be strengthened in future research, so as to facilitate the relevant scientific research and clinical application of DIO.

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Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage

Cited by 41 publications

References 47 publications

Tsg101 Is Involved in the Sorting and Re-Distribution of Glucose Transporter-4 to the Sarcolemma Membrane of Cardiac Myocytes

Tsg101 Is Involved in the Sorting and Re-Distribution of Glucose Transporter-4 to the Sarcolemma Membrane of Cardiac Myocytes

The Dark Side of Nrf2 in the Heart

Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies

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