Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

Fazal, Loubina; Laudette, Marion; Paula-Gomes, Sílvia; Pons, Sandrine; Conte, Caroline; Tortosa, Florence; Sicard, Pierre; Sainte–Marie, Yannis; Bisserier, Malik; Lairez, Olivier; Lucas, Alexandre; Roy, Jérôme; Ghaleh, Bijan; Fauconnier, Jérémy; Mialet‐Perez, Jeanne; Lezoualc’h, Frank

doi:10.1161/circresaha.116.309859

Cited by 91 publications

(115 citation statements)

References 43 publications

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“…Adult ventricular myocytes were obtained from hearts of male C57Bl6J mice at 3 and 20 months, as previously described (Fazal et al, 2017). All animal procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the Directive 2010/63/EU of the European Parliament.…”

Section: Methodsmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H2O2 derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21cip, p16ink4a, and p15ink4b and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies.

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Section: Methodsmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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“…However, a more recent study contradicts these conclusions by demonstrating activation of EPAC1 in mitochondria increases Ca 2ϩ overload and induces cardiomyocyte death. Furthermore, deletion of EPAC1 is cardioprotective against ischemia/reperfusion injury in vivo (289). Mechanistically, activation of EPAC1 by 007-AM stimulates Ca 2ϩ exchange between the endoplasmic reticulum (ER) and the mitochondrion by promoting the formation of a Ca 2ϩ -handling macromolecular complex composed of voltage-dependent anion channel 1 (VDAC1), the chaperone glucose-regulated protein 75 (GRP75), and the inositol-1,4,5-triphosphate (IP 3 ) receptor 1 (IP 3 R1) between the ER and the mitochondrion interface (FIGURE 5) (289).…”

Section: Epac1 Signalosomes At the Cytoskeleton And Other Cellular Locimentioning

confidence: 99%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

162

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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Section: Epac1 and Pathological Cardiac Remodelling Leading To Hfmentioning

confidence: 99%

“…Interestingly, Epac1 expression was markedly increased in various experimental models of myocardial pathological remodelling such as chronic catecholamine infusion and pressure overload induced by thoracic aortic constriction [51][52][53]. Epac1 was also upregulated at the end-stage of non-ischemic or ischemic human HF [52,53]. In support of a role of Epac1 in the progression of cardiac hypertrophy, ectopic overexpression of Epac1 or direct activation of Epac1 with the cAMP analogue, 8-pCPT-cAMP induced various features of cardiac hypertrophy in rat neonatal cardiac myocytes, including myofibrillogenesis, increased cell surface area, protein synthesis, and expression of the atrial natriuretic peptide (ANF) [54].…”

Section: Epac1 and Pathological Cardiac Remodelling Leading To Hfmentioning

confidence: 99%

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The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology

Bouvet

Blondeau

Lezoualc’h

2019

Cells

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The second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) is one of the most important signalling molecules in the heart as it regulates many physiological and pathophysiological processes. In addition to the classical protein kinase A (PKA) signalling route, the exchange proteins directly activated by cAMP (Epac) mediate the intracellular functions of cAMP and are now emerging as a new key cAMP effector in cardiac pathophysiology. In this review, we provide a perspective on recent advances in the discovery of new chemical entities targeting the Epac1 isoform and illustrate their use to study the Epac1 signalosome and functional characterisation in cardiac cells. We summarize the role of Epac1 in different subcompartments of the cardiomyocyte and discuss how cAMP–Epac1 specific signalling networks may contribute to the development of cardiac diseases. We also highlight ongoing work on the therapeutic potential of Epac1-selective small molecules for the treatment of cardiac disorders.

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Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death

Cited by 91 publications

References 43 publications

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology

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