Ketone bodies upregulate endothelial connexin 43 (Cx43) gap junctions

Ho, Chia-Fang; Chan, Kuei-Chuan; Yeh, Hung‐I; Kuo, Jian-Long; Liu, Hung-Jen; Wang, Chi-Young

doi:10.1016/j.tvjl.2013.09.069

Cited by 21 publications

(16 citation statements)

References 24 publications

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“…To test this we examined the amount of CX-43 in neonatal cardiomyocytes incubated with or without the β-OHB. Wt cardiomyocytes incubated with β-OHB showed a 100% increase of CX-43 ( P <0.05) (Fig 5C, quantified in 5D), similar to what was recently reported in endothelial cells[29]. In contrast, β-OHB had no significant impact on CX-43 expression in Tg cardiomyocytes supporting our hypothesis that BDH1 reduces ketone signaling.…”

Section: Resultssupporting

confidence: 89%

“…Recent evidence indicates that ketones can enhance CX-43 protein in endothelial cells via the Extracellular Receptor Kinase (ERK) pathway[29]. We previously noted the deregulation of ERK activity and a loss of CX-43 protein in adult Tg mice[23], and in the present study we detected a 50% down-regulation of CX-43 protein at post-natal day 1 ( P <0.05) (Fig 5A, quantified in 5B).…”

Section: Resultssupporting

confidence: 76%

“…Recent studies demonstrated that β–OHB can enhance CX-43 expression in endothelial cells [29] which we have now also noted in Wt neonatal cardiomyocytes. This suggests that ketones may uniquely modulate the gap junction levels in different cell types.…”

Section: Discussionsupporting

confidence: 78%

“…Thus other factors appear to have an effect on CX-43 expression in culture conditions. In this regard, multiple MAPK pathways have been implicated in the post-transcriptional regulation of CX-43, and these were deregulated in E2F6-Tg mice [34, 29, 23]. It is possible that deregulation of MAPKs may have sensitized E2F6-Tg cardiomyocytes to growth factors in the culture media.…”

Section: Discussionmentioning

confidence: 99%

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E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

et al. 2017

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RationaleThe E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1) is a potential biomarker.ObjectiveTo define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM) with a focus on BDH1.Methods and ResultsWe previously developed transgenic (Tg) mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43) levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70%) in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity) were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB) showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB.ConclusionsThe data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We reveal BDH1 expression as an early biomarker of heart failure and its potential impact, through ketone signaling, on CX-43 levels in E2F6-induced DCM.

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Section: Resultssupporting

confidence: 89%

Section: Resultssupporting

confidence: 76%

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

et al. 2017

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“…Currently, clinicians adopt surgery, chemotherapy, radiotherapy, hormonal therapy, biological molecular targeted therapy, and other comprehensive programs for the treatment of lung cancer patients. However, its local recurrence and distant metastasis are complex biological processes and are major problems plaguing the clinicians (Ho et al 2013). Lung squamous carcinoma is a type of histological lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cx43 gene modification on the proliferation and migration of the human lung squamous carcinoma cell line NCI-H226

Jp¹,

Wei²

2015

Genet. Mol. Res.

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ABSTRACT. In this study, the human lung squamous carcinoma cell line NCI-H226 was transfected with the recombinant plasmid pBudCE4.1_Cx43 to explore the role of the Cx43 gene in cell growth, cell cycle, and tumor migration. pBudCE4.1-Cx43 was transfected into human lung squamous carcinoma NCI-H226 cells using Lipofectamine TM2000. The mRNA and protein expressions of Cx43 in the transfected cells were detected by reverse transcriptase polymerase chain reaction and western blot analysis. The cell-cell communication was detected using the scratch dye tracer method and the cell cycle was detected by flow cytometry. The CCK-8 proliferation, scratch healing, and cell invasion assays were performed to evaluate the effect of the Cx43 gene transfection on the proliferation, migration, and invasive abilities of NCI-H226 cells. Cx43 mRNA and protein expressions and the fluorescence intensity in the scratch healing test were significantly higher in the experimental group than those in the control and blank groups (P < 0.05 and < 0.01, respectively). The CCK-8 proliferation assay and the scratch healing experiment revealed significantly inhibited NCI-H226 cell proliferation (especially 72 h after incubation) and cell migration, respectively, in the experimental group, compared to the control and 13110-13119 (2015) blank groups (P < 0.001 and <0.05, respectively). The transwell chamber test showed a statistically significant decrease in the invasive ability of NCI-H226 cells in the experimental group (P < 0.05). Therefore, Cx43 gene transfection could inhibit the migration of human lung squamous carcinoma cell line NCI-H226, thereby inhibiting tumor cell proliferation.

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Resveratrol Enhances Chemosensitivity in Mouse Melanoma Model Through Connexin 43 Upregulation

Cheng

Chang

et al. 2014

Environmental Toxicology

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Although current studies indicate that resveratrol exhibits potential antitumor activities, the precise mechanisms of its beneficial effects combined with chemotherapy are not fully understood. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of resveratrol and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Gap junctions mediate cell communication by allowing the passage of molecules from one cell to another. Connexin (Cx) 43 is ubiquitous and reduced in a variety of tumor cells. Cx43 may influence the response of tumor cells to treatments by facilitating the passage of antitumor drugs or death signals between neighboring tumor cells. Following resveratrol treatment, dose-dependent upregulation of Cx43 expressions was observed. In addition, gap junction intercellular communication was increased. To study the mechanism underlying these resveratrol-induced Cx43 expressions, we found that resveratrol induced a significant increase in mitogen-activated protein kinases (MAPK) signaling pathways. The MAPK inhibitors significantly reduced the expression of Cx43 protein after resveratrol treatment. Specific knockdown of Cx43 resulted in a reduction of cell death after resveratrol and cisplatin treatment. Our results suggest that treatment of resveratrol in tumor leads to increase Cx43 gap junction communication and enhances the combination of resveratrol and cisplatin therapeutic effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 877-886, 2015.

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Ketone bodies upregulate endothelial connexin 43 (Cx43) gap junctions

Cited by 21 publications

References 24 publications

E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

Effects of Cx43 gene modification on the proliferation and migration of the human lung squamous carcinoma cell line NCI-H226

Resveratrol Enhances Chemosensitivity in Mouse Melanoma Model Through Connexin 43 Upregulation

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