Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis

Monceau, Virginie; Llach, Anna; Azria, D.; Bridier, A.; Petit, Benoît; Mazevet, Marianne; Strup-Perrot, Carine; To, Thi-Hong-Van; Calmels, L.; Germaini, Marie-Michèle; Gourgou, Sophie; Fenoglietto, P.; Bourgier, C.; Gómez, Ana-María; Escoubet, Brigitte; Dörr, Wolfgang; Haagen, Julia; Deutsch, Éric; Morel, Éric; Vozenin, Marie-Catherine

doi:10.1016/j.radonc.2014.01.025

Cited by 26 publications

(30 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…52 Of particular interest, a recent study identified EPAC1 as a potential mediator of radiation-induced hypertrophy in primary cardiomyocytes suggesting that cAMP-GEF is involved in regulating the side effects of anticancer treatment. 128 In 2008, the finding that β-ARs activated EPAC1 to trigger hypertrophy in a PKA-independent manner in isolated adult rat cardiomyocytes led to the hypothesis that, in addition to the classic cAMP/PKA pathway, β-AR stimulation under certain pathophysiological circumstances might switch on the EPACsignaling pathway. 17 This assumption has been partially confirmed in vivo using full EPAC1 knockout mice.…”

Section: Epac and Cardiac Hypertrophymentioning

confidence: 99%

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

147

143

View full text Add to dashboard Cite

C yclic adenosine 3′,5′-monophosphate (cAMP) is one of the most studied signaling molecules that plays a critical role in cellular responses to extracellular stimuli in the cardiovascular system. It controls a wide range of biological effects, including cell proliferation, differentiation, and apoptosis. 1 cAMP is produced from ATP by transmembrane adenylyl cyclase on activation of Gs-coupled G protein-coupled receptors. 2In addition, soluble adenylyl cyclase is a second intracellular source of cAMP and can be activated by divalent cations in various subcellular compartments.3 The intracellular level of cAMP depends not only on its production by adenylyl cyclase but also its degradation by a large family of cAMP phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP into 5′-AMP. 4 PDEs are key actors in limiting the spread of cAMP and seem critical for the formation of dynamic microdomains that confer specific response to various hormones. 4 Besides specialized membrane structures that may also limit cAMP diffusion, A-kinase anchoring proteins function to tether cAMP effectors and PDEs enzymes into defined cellular compartments and, therefore, maintain localized pools of cAMP to control the cellular actions of the second messenger. 5Until recently, the intracellular effects of cAMP were attributed to the activation of protein kinase A (PKA) and cyclic nucleotide-gated ion channels. In 1998, a family of novel cAMP effector proteins named exchange proteins directly activated by cAMP (EPACs) was discovered. 6,7 The EPAC protein family is composed of EPAC1 and EPAC2, which act as guanine-nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2, and function in a PKA-independent manner. 6,7 On binding to cAMP, EPAC promotes the exchange of GDP for GTP, thereby inducing the activation of the small G protein Rap.8 In contrast, Rap-GTPase-activating proteins enhance the intrinsic GTP hydrolysis activity of Rap leading to GTPase inactivation. 9The cycling of Rap between its inactive and active states provides a mechanism to regulate the binding to effector proteins.The discovery of EPAC proteins has broken the dogma surrounding cAMP and PKA, and uncovered new perspectives for the understanding of cAMP signaling in the cardiovascular system. The functions of these cAMP-sensitive GEFs in various subcellular compartments and cellular contexts are currently being unraveled, but given the availability of EPAC-specific ligands and engineered mouse models, a large body of evidence indicates that EPAC proteins are involved in multiple biological actions of cAMP, such as cardiac hypertrophy and vascular inflammation. In this review, after a description of EPAC protein structures and mechanism of activation, we discuss recent advances in the discovery of novel pharmacological modulators of EPAC (Figure 1). We provide an overview of the roles of EPAC proteins, their signalosome and compartmentation in cardiovascular function and diseases. We also discuss the therapeutic potential of EPAC ligands in the t...

show abstract

Section: Epac and Cardiac Hypertrophymentioning

confidence: 99%

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

147

143

View full text Add to dashboard Cite

show abstract

“…While cardiac function was normal at 2 and 6 weeks, it was significantly depressed 15 weeks Saline vs. 3096.0±238.2 Dox; at 6 weeks 3009.5±211.8 in Saline vs 2943.2±145.7 Dox; at 15 weeks 3454.7±176.0 Saline vs 3288.4±114.4 Dox).The decrease in contractile function at 15 weeks post treatment could be due to development of fibrosis, or to a defect on the cardiomyocyte contraction itself. We previously showed that cardiac fibrosis was involved in heart dysfunction after radiotherapy[26]. Thus we wanted to investigate whether this mechanism was also present after Dox treatment.…”

mentioning

confidence: 98%

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

Llach

Mazevet

Matéo

et al. 2019

Journal of Molecular and Cellular Cardiology

Self Cite

View full text Add to dashboard Cite

Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks after the last injection. While normal at 2 and 6 weeks, ejection fraction was significantly reduced at 15 weeks. In order to evaluate the underlying mechanisms, we measured [Ca 2+ ] i transients by confocal microscopy and action potentials (AP) by patch-clamp technique in cardiomyocytes isolated at these times. Three phases were observed: 1/ depression and slowing of the [Ca 2+ ] i transients at 2 weeks after treatment, with occurrence of proarrhythmogenic Ca 2+ waves, 2/ compensatory state at 6 weeks, and 3/ depression on [Ca 2+ ] i transients and cell contraction at 15 weeks, concomitant with invivo defects. These [Ca 2+ ] i transient alterations were observed without cellular hypertrophy or AP prolongation and mirrored the sarcoplasmic reticulum (SR) Ca 2+ load variations. At the molecular level, this was associated with a decrease in the sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) expression and enhanced RyR2 phosphorylation at the protein kinase A (PKA, pS2808) site (2 and 15 weeks). RyR2 phosphorylation at the Ca 2+ /calmodulin dependent protein kinase II (CaMKII, pS2814) site was enhanced only at 2 weeks, coinciding with the higher incidence of proarrhythmogenic Ca 2+ waves. Our study highlighted, for the first time, the progression of Dox treatment-induced alterations in Ca 2+ handling and identified key components of the underlying Dox cardiotoxicity. These findings should be helpful to understand the early-, intermediate-, and late-cardiotoxicity already recorded in clinic in order to prevent or treat at the subclinical level.

show abstract

“…Correlations of unknown significance were seen between total LV ECV and maximum heart doses, as well as mid-LV ECV and ventricular doses, where lower ECV values correlated with higher radiation doses ( Tables 4 and 5 ). It should be noted that the changes in LVMI without a corresponding change in ECV may be due to increased cardiomyocyte size causing hypertrophy, without or before reactive or replacement fibrosis, as has been seen post-radiation in some patients and preclinical models ( 44 , 45 ). Total heart or ventricular radiation doses did not correlate with GLS values ( Tables 4 and 5 ).…”

Section: Discussionmentioning

confidence: 97%

A Pilot Study of Cardiac MRI in Breast Cancer Survivors After Cardiotoxic Chemotherapy and Three-Dimensional Conformal Radiotherapy

et al. 2020

View full text Add to dashboard Cite

Purpose/Objectives: Node-positive breast cancer patients often receive chemotherapy and regional nodal irradiation. The cardiotoxic effects of these treatments, however, may offset some of the survival benefit. Cardiac magnetic resonance (CMR) is an emerging modality to assess cardiac injury. This is a pilot trial assessing cardiac damage using CMR in patients who received anthracycline-based chemotherapy and three-dimensional conformal radiotherapy (3DCRT) regional nodal irradiation using heart constraints. Materials and Methods: Node-positive breast cancer patients (2000-2008) treated with anthracycline-based chemotherapy and 3DCRT regional nodal irradiation (including the internal mammary chain nodes) with heart ventricular constraints (V25 < 10%) were invited to participate. Cardiac tissues were contoured and analyzed separately for whole heart (pericardium) and for combined ventricles and left atrium (myocardium). CMR obtained ventricular function/dimensions, late gadolinium enhancement (LGE), global longitudinal strain (GLS), and extracellular volume fraction (ECV) as measures of cardiac injury and/or early fibrosis. CMR parameters were correlated with dose-volume constraints using Spearman correlations. Results: Fifteen left-sided and five right-sided patients underwent CMR. Median diagnosis age was 50 (32-77). No patients had baseline cardiac disease before regional nodal irradiation. Median time after 3DCRT was 8.3 years (5.2-14.4). Median left-sided mean heart dose (MHD) was 4.8 Gy (1.1-11.2) and V25 was 5.7% (0-12%). Median left ventricular ejection fraction (LVEF) was 63%. No abnormal LGE was observed.

show abstract

Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis

Cited by 26 publications

References 47 publications

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity

A Pilot Study of Cardiac MRI in Breast Cancer Survivors After Cardiotoxic Chemotherapy and Three-Dimensional Conformal Radiotherapy

Contact Info

Product

Resources

About