TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

Cheng, Kai‐Chun; Chang, Wen-Teng; Kuo, Feng Yu; Chen, Zhih‐Cherng; Li, Yingxiao; Cheng, Juei‐Tang

doi:10.1038/s41598-019-40002-0

Cited by 39 publications

(32 citation statements)

References 47 publications

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“…13 Intracellular Reactive Oxygen Species (ROS) and Superoxide Measurement Intracellular ROS generation during hyperglycemia in HepG2 cells was measured by dihydroethidium (DHE) (Thermo Fisher Scientific Inc., Rockford, IL, USA) following a previous study. 16 Cells were treated with high glucose plus tiron (1 µM or 5 µM) for 48 h. Tiron (4,5-dihydroxy-1,3-benzenedisulfonic; Sigma-Aldrich) is a membranepermeable antioxidant, 17 which has been shown to have a hepatoprotective effect. 18 Cells treated with Tiron at the indicated concentrations did not show noticeable change in the cell growth.…”

Section: Small Interfering Rna (Sirna)mentioning

confidence: 99%

<p>Promotion of Adropin Expression by Hyperglycemia Is Associated with STAT3 Activation in Diabetic Rats</p>

Kuo¹,

Cheng²,

Li³

et al. 2020

DMSO

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Background: Adropin is a secreted polypeptide that has been demonstrated to play an important role in energy homeostasis and lipid metabolism. Signal transducer and activator of transcription 3 (STAT3) may promote the transcription of target genes including adropin. In the current study, we investigated the effect of adropin on glucose metabolism in diabetic rats and the mechanism that governs this effect was subsequently assessed. Materials and Methods: Rats received a single injection of streptozotocin to induce type 1 diabetes. The diabetic rats were treated with insulin or phloridzin, another antidiabetic agent through inhibition of glucose reabsorption, for 7 days. Plasma glucose levels and adropin levels were measured. The interaction between STAT3 and adropin was evaluated using the human hepatoma HepG2 cell line. HepG2 cells were pretreated with the specific antagonist Stattic or with STAT3-specific siRNAs to knockout STAT3. Changes in energy homeostasisassociated gene expression were measured using real-time PCR. The protein expression levels of pSTAT3 and STAT3 were measured using Western blotting. Results: In diabetic rats, the serum concentrations of adropin were increased in the vehicletreated group and decreased in the insulin-or phloridzin-treated group. In liver tissues, the Enho expression level and the activity of STAT3 also showed similar tendencies. After HepG2 cells were treated with medium containing high glucose, the ratio of p-STAT3 to STAT3, Enho mRNA levels and reactive oxygen species expression levels in HepG2 cells were significantly increased in conjunction with increased glucose levels. The effect was inhibited after pretreatment with Stattic or knockdown with STAT3-specific siRNAs. Conclusion: STAT3 is involved in the genetic regulation of adropin, increasing the levels of circulating adropin and promoting Enho expression in the livers of diabetic rats.

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Section: Small Interfering Rna (Sirna)mentioning

confidence: 99%

<p>Promotion of Adropin Expression by Hyperglycemia Is Associated with STAT3 Activation in Diabetic Rats</p>

Kuo¹,

Cheng²,

Li³

et al. 2020

DMSO

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“…As a starting point, initial proof-of-concept experiments were undertaken in rat H9c2 cardiomyocytes 20 , a low-cost, tractable model used most typically in toxicology research and early-stage cardiac drug discovery. Notably, this body of work includes more than 300 studies of anthracycline toxicity [21][22][23][24][25][26][27][28][29][30][31][32][33][34] as well as high-throughput, phenotypedriven screens for novel cardioprotective agents 35,36 . Viability as measured by the CellTiter-Glo ATP generation assay was markedly impaired by DOX, with half-maximal effects at 150-250 nM at 24 and 48 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the widely reported utility of H9c2 cells [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] , their applicability as a predictive model in cardiac drug development is compromised by their continuous proliferation, lack of the sodium/calcium exchanger NCX1, lack of beating, and skeletal muscle potential 20,38,39 . Moreover, explicit disparities have been reported in drug effects relating to cardioprotection and cardiotoxicity in this model, compared with human cells 40,41 .…”

Section: Inhibitors Of Map4k4 Confer Protection From Dox In Human Pscmentioning

confidence: 99%

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Golforoush

Narasimhan

Guerrero

et al. 2020

Sci Rep

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Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death. With earlier diagnosis and improved treatments for cancer, cardiovascular disease has become the main alternative cause of death in cancer survivors 1-4. This heightened risk is ascribable to the cardiac toxicity of several routine anti-cancer agents including, especially, anthracyclines like doxorubicin (DOX) 5. Though some relief can result from standard heart failure medications, no approved therapy apart from the iron chelator dexrazoxane addresses the responsible cytotoxic mechanisms and effector pathways operating in the damaged cardiomyocytes. For anthracyclines, these include diverse reported mediators-binding to nuclear topoisomerase 2β, thereby triggering DNA double-strand breaks, p53-dependent apoptosis, mitochondrial dysfunction, reactive oxygen species, and programmed iron-dependent cell death (ferroptosis) 1,6,7. Cardiotoxicity can be acute, early, or late; early intervention based on subclinical abnormalities may be key to averting the delayed or cumulative effects 8. Notably, acute toxicity is seen in up to 30% of patients receiving anthracyclines, soon after infusion 4. Current cardioprotection trials in cancer rely chiefly on routine heart failure medications (ACE inhibitors, β-blockers, angiotensin receptor blockers), which mitigate the symptoms and signs, with little or no demonstrated impact on cardiomyocyte death. Therapeutic progress has been hampered, in part, by the failure of animal models alone to predict clinical success in cardioprotection. For instance, nearly all strategies for protection in ischemic heart disease, a more intensively studied indication, have failed between phases I and I...

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“…To study the effect of different concentrations of glucose, DMEM media with low glucose is often used although, H9c2 cells were cultured in DMEM media containing 25 mM . DMEM media with 5.5 mM glucose is suggestible as it corresponds to 100 mg/dL and is similar to the normal blood glucose level of human.…”

Section: Methodsmentioning

confidence: 99%

Trolox prevents high glucose‐induced apoptosis in rat myocardial H9c2 cells by regulating GLUT‐4 and antioxidant defense mechanism

2019

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Redox imbalance due to hyperglycemia is a causative factor for an increased generation of reactive oxygen species (ROS) that leads to mitochondrial dysfunction and the release of cytochrome-c. The aim of the present study is to elucidate the functional role of oxidative stress (OS) in the induction of apoptosis in H9c2 cells in the hyperglycemic state through glucose transporter-4 (GLUT-4) regulation and antioxidant status. H9c2 cells were incubated with 15, 24, and 33 mM glucose for 24, 48, and 72 hr to induce hyperglycemic stress. Hyperglycemic episodes have significantly influenced GLUT-4 mRNA regulation, depleted glutathione (GSH) and its associated enzymes, reduced cellular antioxidant enzymes (AOEs), caused nuclear condensation, and induced apoptosis by activating caspase-9 and 3 and annexin V binding in a concentration and duration-dependent manner. Trolox pretreatment significantly enhanced the GLUT-4 mRNA and antioxidant defense mechanism, suppressed nuclear condensation, and prevented cytochrome-c release, thereby reducing mitochondrial-dependent apoptosis. The present study shows that the toxic effect of high glucose is significantly regulated and that OS induction can be prevented through a water-soluble vitamin E analog "Trolox" treatment.

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TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

Cited by 39 publications

References 47 publications

<p>Promotion of Adropin Expression by Hyperglycemia Is Associated with STAT3 Activation in Diabetic Rats</p>

<p>Promotion of Adropin Expression by Hyperglycemia Is Associated with STAT3 Activation in Diabetic Rats</p>

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4

Trolox prevents high glucose‐induced apoptosis in rat myocardial H9c2 cells by regulating GLUT‐4 and antioxidant defense mechanism

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