Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium

Major, Jennifer L.; Salih, Maysoon; Tuana, Balwant S.

doi:10.1016/j.yjmcc.2015.04.026

Cited by 5 publications

(12 citation statements)

References 46 publications

(64 reference statements)

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“…E2F6 expression in postnatal myocardium led to dose dependent DCM associated with decreased levels of CX-43[23,24]. Our previous microarray results predicted the up-regulation of Bdh1 in E2F6-Tg hearts thus we performed RT-q-PCR on mRNA collected from Wt and Tg pup hearts for validation.…”

Section: Resultsmentioning

confidence: 99%

“…BDH1 protein was barely detectable in Wt pup hearts but was markedly upregulated by 890% ( P <0.05) in E2F6 Tg hearts at post-natal day 1 (P1) (Fig 1B, quantified in 1C). Since BDH1 is up-regulated in the failing adult human heart [10] we examined its expression at 6 weeks of age, at which time Tg mice show full onset of DCM[24]. Western blot analysis did not reveal any difference in BDH1 level between Tg and Wt hearts at this time (Fig 1B, quantified in 1C).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, in E2F6-Tg hearts, BDH1 expression appears to be maximally expressed as early as P1 with this level maintained at P7, 3 weeks, and 6 weeks. It should be noted that symptoms of DCM arise as early as 2 weeks in E2F6-Tg mice[24], thus BDH1 is markedly elevated prior to the early development of DCM and maintained at this level into adulthood (Fig 1D). …”

Section: Resultsmentioning

confidence: 99%

“…Previously described Tg mice with cardiac specific expression of E2F6 (under control of the α-Myosin heavy chain promoter) (B6C3F1) were bred with WT (B6C3F1) mice [23,24]. All animal work was conducted according to the University of Ottawa’s institutional animal care committee guidelines.…”

Section: Methodsmentioning

confidence: 99%

“…E2F6 is a unique E2F family member which is believed to repress E2F responsive genes independently of Rb [21, 22] (Gaubatz, Wood, & Livingston, 1998; Trimarchi, Fairchild, Wen, & Lees, 2001) . We previously examined the contribution of the E2F pathway in post-natal mouse myocardium by cardiac specific expression of E2F6 which led to the early-onset of dilated cardiomyopathy (DCM) without hypertrophy or apoptosis [23, 24]. Contrary to expectation, E2F6-Tg mice showed activation of E2F responsive genes [23].…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

et al. 2017

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E2F6 protein levels modulate drug induced apoptosis in cardiomyocytes

Major

Salih

Tuana

2017

Cellular Signalling

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Resveratrol Attenuates High Glucose-Induced Vascular Endothelial Cell Injury by Activating the E2F3 Pathway

Ding

Yao

Zhu

et al. 2020

BioMed Research International

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Type 2 diabetes mellitus (T2DM) is the most common metabolic disease. High glucose-induced macrovascular disease and microangiopathy are major complications of diabetes. E2F3, a member of the E2F transcription factor family, is closely related to cardiovascular diseases. Resveratrol, a nonflavonoid polyphenolic compound widely found in plants, has been shown to have cardiovascular protection. However, there are few studies on whether resveratrol can effectively treat diabetic angiopathy, and the specific mechanism involved needs further study. This study investigated whether E2F3 transcription factors are involved in the process of vascular endothelial injury induced by high glucose and observed its effects on the proliferation of vascular endothelial cells. Then, it analyzed whether resveratrol can inhibit high glucose-induced vascular endothelial cell injury by regulating the E2F3 pathway. We demonstrated that the expression level of the E2F3 transcription factor was significantly inhibited in high glucose state. Resveratrol inhibited high glucose-induced vascular endothelial cell injury by upregulating the E2F3 pathway. High glucose can induce vascular endothelial injury by inhibiting E2F3 gene expression, while resveratrol can inhibit high glucose-induced vascular endothelial injury by activating the E2F3 pathway.

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Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium

Cited by 5 publications

References 46 publications

E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy

E2F6 protein levels modulate drug induced apoptosis in cardiomyocytes

Resveratrol Attenuates High Glucose-Induced Vascular Endothelial Cell Injury by Activating the E2F3 Pathway

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