Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium
| Autor: | Jennifer L. Major, Maysoon Salih, Balwant S. Tuana |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Cardiomyopathy
Dilated MAPK/ERK pathway medicine.medical_specialty Adrenergic receptor Cell Survival Down-Regulation E2F6 Transcription Factor Adrenergic AKT1 Cardiomegaly Mice Transgenic Biology Retinoblastoma Protein Internal medicine Receptors Adrenergic beta medicine Animals RNA Messenger Extracellular Signal-Regulated MAP Kinases Protein kinase A Receptor Molecular Biology Kinase Myocardium Calcium-Binding Proteins Isoproterenol Dilated cardiomyopathy medicine.disease Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotide Phosphodiesterases Type 4 Enzyme Activation src-Family Kinases Endocrinology Cardiology and Cardiovascular Medicine Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 84:179-190 |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2015.04.026 |
| Popis: | The E2F/Pocket protein (Rb) pathway regulates cell growth, differentiation, and death by modulating gene expression. We previously examined this pathway in the myocardium via manipulation of the unique E2F repressor, E2F6, which is believed to repress gene activity independently of Rb. Mice with targeted expression of E2F6 in postnatal myocardium developed dilated cardiomyopathy (DCM) without hypertrophic growth. We assessed the mechanisms of the apparent failure of compensatory hypertrophic growth as well as their response to the β-adrenergic agonist isoproterenol. As early as 2 weeks, E2F6 transgenic (Tg) mice present with dilated thinner left ventricles and significantly reduced ejection fraction and fractional shortening which persists at 6 weeks of age, but with no apparent increase in left ventricle weight: body weight (LVW:BW). E2F6-Tg mice treated with isoproterenol (6.1 mg/kg/day) show double the increase in LVW:BW than their Wt counterparts (32% vs 16%, p-value: 0.007). Western blot analysis revealed the activation of the adrenergic pathway in Tg heart tissue under basal conditions with ~2-fold increase in the level of β2-adrenergic receptors (p-value: 8.9E-05), protein kinase A catalytic subunit (PKA-C) (p-value: 0.0176), activated c-Src tyrosine-protein kinase (p-value: 0.0002), extracellular receptor kinase 2 (ERK2) (p-value: 0.0005), and induction of the anti-apoptotic protein Bcl2 (p-value 0. 0.00001). In contrast, a ~60% decrease in the cardiac growth regulator: AKT1 (p-value 0.0001) and a ~four fold increase in cyclic AMP dependent phosphodiesterase 4D (PDE4D), the negative regulator of PKA activity, were evident in the myocardium of E2F6-Tg mice. The expression of E2F3 was down-regulated by E2F6, but was restored by isoproterenol. Further, Rb expression was down-regulated in Tg mice in response to isoproterenol implying a net activation of the E2F pathway. Thus the unique regulation of E2F activity by E2F6 renders the myocardium hypersensitive to adrenergic stimulus resulting in robust hypertrophic growth. These data reveal a novel interplay between the E2F pathway, β2-adrenergic/PKA/PDE4D, and ERK/c-Src axis in fine tuning the pathological hypertrophic growth response. E2F6 deregulates E2F3 such that pro-hypertrophic growth and survival are enhanced via β2-adrenergic signaling however this response is outweighed by the induction of anti-hypertrophic signals so that left ventricle dilation proceeds without any increase in muscle mass. |
| Databáze: | OpenAIRE |
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