Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death
Open accessAbstract
Rationale: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood. Objective: To investigate the role of MitEpac1 (mitochondrial exchange protein directly activated by cAMP 1) in ischemia/reperfusion injury. Methods and Results: We show that Epac1 (exchange protein directly activated by cAMP 1) genetic ablation ( Epac1 −/− ) protects against experimental myocardial ischemia/reperfusion injury with reduced infarct size and cardiomyocyte apoptosis. As observed in vivo, Epac1 inhibition prevents hypoxia/reoxygenation–induced adult cardiomyocyte apoptosis. Interestingly, a deleted form of Epac1 in its mitochondrial-targeting sequence protects against hypoxia/reoxygenation–induced cell death. Mechanistically, Epac1 favors Ca 2+ exchange between the endoplasmic reticulum and the mitochondrion, by increasing interaction with a macromolecular complex composed of the VDAC1 (voltage-dependent anion channel 1), the GRP75 (chaperone glucose-regulated protein 75), and the IP3R1 (inositol-1,4,5-triphosphate receptor 1), leading to mitochondrial Ca 2+ overload and opening of the mitochondrial permeability transition pore. In addition, our findings demonstrate that MitEpac1 inhibits isocitrate dehydrogenase 2 via the mitochondrial recruitment of CaMKII (Ca 2+ /calmodulin-dependent protein kinase II), which decreases nicotinamide adenine dinucleotide phosphate hydrogen synthesis, thereby, reducing the antioxidant capabilities of the cardiomyocyte. Conclusions: Our results reveal the existence, within mitochondria, of different cAMP–Epac1 microdomains that control myocardial cell death. In addition, our findings suggest Epac1 as a promising target for the treatment of ischemia-induced myocardial damage.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
RAPGEF3 (EPAC1) appears to trigger PTPC opening by increasing mitochondrial Ca2+ levels through interaction with VDAC1, HSPA9, and ITPR1, and knockout of Rapgef3 protects mice against myocardial ischemia/reperfusion injury.
“Finally, rap guanine nucleotide exchange factor 3 (RAPGEF3; best known as EPAC1) appears to trigger PTPC opening by increasing mitochondrial Ca2+ levels through interaction with VDAC1, heat shock protein family A (Hsp70) member 9 (HSPA9; best known as GRP75), and inositol 1,4,5-trisphosphate receptor type 1 (ITPR1; best known as IP3R1), and the knockout of Rapgef3 protects mice against myocardial”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [421]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The thioredoxin antioxidant system
Lu, J., & Holmgren, A. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.036 · Cited by 2,055 · see citing works
Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP
de Rooij, J., Zwartkruis, F. J. T., Verheijen, M. H. G., Cool, R. H., Nijman, S. M. B., Wittinghofer, A., & Bos, J. L. (1998) · Nature · doi:10.1038/24884 · Cited by 1,970 · see citing works
Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels
Szabadkai, G., Bianchi, K., Várnai, P., De Stefani, D., Wieckowski, M. R., Cavagna, D., Nagy, A. I., Balla, T., & Rizzuto, R. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200608073 · Cited by 1,413 · see citing works
A Family of cAMP-Binding Proteins That Directly Activate Rap1
Kawasaki, H., Springett, G. M., Mochizuki, N., Toki, S., Nakaya, M., Matsuda, M., Housman, D. E., & Graybiel, A. M. (1998) · Science · doi:10.1126/science.282.5397.2275 · Cited by 1,360 · see citing works
Pan, X., Liu, J., Nguyen, T. T. M., Liu, C., Sun, J., Teng, Y., Fergusson, M. M., Rovira, I. I., Allen, M. D., Springer, D., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2868 · Cited by 645 · see citing works
Cardiac Mitochondria and Reactive Oxygen Species Generation
Chen, Y., & Zweier, J. L. (2014) · Circulation Research · doi:10.1161/circresaha.114.300559 · Cited by 606 · see citing works
Jo, S.-H., Son, M.-K., Koh, H.-J., Lee, S.-M., Song, I.-H., Kim, Y.-O., Lee, Y.-S., Jeong, K.-S., Kim, W. B., Park, J.-W., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010120200 · Cited by 536 · see citing works
Bernardi, P., & Lisa, F. D. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.09.023 · Cited by 499 · see citing works
Cyclic AMP Produced inside Mitochondria Regulates Oxidative Phosphorylation
Acín‐Pérez, R., Salazar, E., Kamenetsky, M., Buck, J., Levin, L. R., & Manfredi, G. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.01.012 · Cited by 465 · see citing works
Timmins, J. M., Özcan, L., Seimon, T. A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel‐Duby, R., Olson, E. N., Anderson, M. E., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38857 · Cited by 422 · see citing works
CaMKII determines mitochondrial stress responses in heart
Joiner, M.-L. A., Koval, O. M., Li, J., He, B. J., Allamargot, C., Gao, Z., Luczak, E. D., Hall, D. D., Fink, B. D., Chen, B., et al. (2012) · Nature · doi:10.1038/nature11444 · Cited by 411 · see citing works
Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure
Nickel, A. G., von Hardenberg, A., Hohl, M., Löffler, J., Kohlhaas, M., Becker, J., Reil, J., Kazakov, A., Bonnekoh, J., Stadelmaier, M., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.008 · Cited by 380 · see citing works
Ong, S., Samangouei, P., Kalkhoran, S. B., & Hausenloy, D. J. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.11.005 · Cited by 323 · see citing works
Paillard, M., Tubbs, E., Thiébaut, P., Gomez, L., Fauconnier, J., Silva, C. C. D., Teixeira, G., Mewton, N., Belaïdi, E., Durand, A., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.001225 · Cited by 279 · see citing works
Self-citationPereira, L., Metrich, M., Fernández‐Velasco, M., Lucas, A., Leroy, J., Perrier, R., Morel, É., Fischmeister, R., Richard, S., Bénitah, J., et al. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.133066 · Cited by 213 · see citing works
Self-citationEpac Mediates β-Adrenergic Receptor–Induced Cardiomyocyte Hypertrophy
Metrich, M., Lucas, A., Gastineau, M., Samuel, J., Heymes, C., Morel, É., & Lezoualc’h, F. (2008) · Circulation Research · doi:10.1161/circresaha.107.164947 · Cited by 207 · see citing works
Self-citationCyclic AMP is both a pro‐apoptotic and anti‐apoptotic second messenger
Insel, P. A., Zhang, L., Murray, F., Yokouchi, H., & Zambon, A. C. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2011.02273.x · Cited by 204 · see citing works
β-Adrenergic stimulation and myocardial function in the failing heart
El‐Armouche, A., & Thomas Eschenhagen, A. (2008) · Heart Failure Reviews · doi:10.1007/s10741-008-9132-8 · Cited by 202 · see citing works
Trollinger, D. R., Cascio, W. E., & Lemasters, J. J. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7042 · Cited by 199 · see citing works
cAMP signaling in subcellular compartments
Lefkimmiatis, K., & Zaccolo, M. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.03.008 · Cited by 194 · see citing works
Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease
Lezoualc’h, F., Fazal, L., Laudette, M., & Conte, C. (2016) · Circulation Research · doi:10.1161/circresaha.115.306529 · Cited by 189 · see citing works
Self-citationBenedetto, G. D., Scalzotto, E., Mongillo, M., & Pozzan, T. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.003 · Cited by 184 · see citing works
Epac2 Mediates Cardiac β1-Adrenergic–Dependent Sarcoplasmic Reticulum Ca 2+ Leak and Arrhythmia
Pereira, L., Cheng, H., Lao, D. H., Na, L., van Oort, R. J., Brown, J. H., Wehrens, X. H. T., Chen, J., & Bers, D. M. (2013) · Circulation · doi:10.1161/circulationaha.12.148619 · Cited by 180 · see citing works
Cell Cycle-dependent Subcellular Localization of Exchange Factor Directly Activated by cAMP
Qiao, J., Mei, F. C., Popov, V. L., Vergara, L. A., & Cheng, X. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203571200 · Cited by 178 · see citing works
Scarabelli, T. M., Stephanou, A., Pasini, E., Comini, L., Raddino, R., Knight, R. A., & Latchman, D. S. (2002) · Circulation Research · doi:10.1161/01.res.0000015224.07870.9a · Cited by 166 · see citing works
Time Course and Mechanism of Myocardial Catecholamine Release During Transient Ischemia In Vivo
Lameris, T. W., de Zeeuw, S., Alberts, G., Boomsma, F., Duncker, D. J., Verdouw, P. D., Veld, A. J. M. I. '., & van den Meiracker, A. H. (2000) · Circulation · doi:10.1161/01.cir.101.22.2645 · Cited by 147 · see citing works
The inner and outer compartments of mitochondria are sites of distinct cAMP/PKA signaling dynamics
Lefkimmiatis, K., Leronni, D., & Hofer, A. M. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201303159 · Cited by 143 · see citing works
8‐pCPT‐2′‐O‐Me‐cAMP‐AM: An Improved Epac‐Selective cAMP Analogue
Vliem, M. J., Ponsioen, B., Schwede, F., Pannekoek, W., Riedl, J., Kooistra, M. R. H., Jalink, K., Genieser, H., Bos, J. L., & Rehmann, H. (2008) · ChemBioChem · doi:10.1002/cbic.200800216 · Cited by 117 · see citing works
Protein Kinase A as Another Mediator of Ischemic Preconditioning Independent of Protein Kinase C
Sanada, S., Asanuma, H., Tsukamoto, O., Minamino, T., Node, K., Takashima, S., Fukushima, T., Ogai, A., Shinozaki, Y., Fujita, M., et al. (2004) · Circulation · doi:10.1161/01.cir.0000133390.12306.c7 · Cited by 112 · see citing works
Courilleau, D., Bisserier, M., Jullian, J., Lucas, A., Bouyssou, P., Fischmeister, R., Blondeau, J., & Lezoualc’h, F. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.422956 · Cited by 110 · see citing works
Self-citationWang, Z., Liu, D., Varin, A., Nicolas, V, Courilleau, D., Mateo, P., Caubere, C., Rouet, P., Gomez, A.-M., Vandecasteele, G., et al. (2016) · Cell Death & Disease · doi:10.1038/cddis.2016.106 · Cited by 106 · see citing works
Exchange protein directly activated by cAMP 1 promotes autophagy during cardiomyocyte hypertrophy
Laurent, A., Bisserier, M., Lucas, A., Tortosa, F., Roumieux, M., de Régibus, A., Swiader, A., Sainte–Marie, Y., Heymes, C., Vindis, C., et al. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu242 · Cited by 93 · see citing works
Self-citationMukai, E., Fujimoto, S., Sato, H., Oneyama, C., Kominato, R., Sato, Y., Sasaki, M., Nishi, Y., Okada, M., & Inagaki, N. (2010) · Diabetes · doi:10.2337/db10-0021 · Cited by 92 · see citing works
The cAMP binding protein Epac regulates cardiac myofilament function
Cazorla, O., Lucas, A., Poirier, F., Lacampagne, A., & Lezoualc’h, F. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812536106 · Cited by 86 · see citing works
Self-citationLow-pressure reperfusion alters mitochondrial permeability transition
Bopassa, J.-C., Michel, P., Gateau-Roesch, O., Ovize, M., & Ferrera, R. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01081.2004 · Cited by 82 · see citing works
Measurements of mitochondrial calcium in vivo
Pozzan, T., & Rudolf, R. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.11.012 · Cited by 75 · see citing works
Pereira, L., Rehmann, H., Lao, D. H., Erickson, J. R., Bossuyt, J., Chen, J., & Bers, D. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416163112 · Cited by 73 · see citing works
Epac in cardiac calcium signaling
Ruiz‐Hurtado, G., Morel, É., Domínguez‐Rodríguez, A., Llach, A., Lezoualc’h, F., Bénitah, J., & Gomez, A. M. (2012) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2012.11.021 · Cited by 71 · see citing works
Self-citationBerthouze, M., Lucas, A., Saulière, A., Sin, Y. Y., Laurent, A., Galès, C., Baillie, G. S., & Lezoualc’h, F. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.12.007 · Cited by 67 · see citing works
Self-citationAppukuttan, A., Kasseckert, S. A., Micoogullari, M., Flacke, J.-P., Kumar, S., Woste, A., Abdallah, Y., Pott, L., Reusch, H. P., & Ladilov, Y. V. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr306 · Cited by 61 · see citing works
Epac-Rap Signaling Reduces Oxidative Stress in the Tubular Epithelium
Stokman, G., Qin, Y., Booij, T. H., Ramaiahgari, S., Lacombe, M., Dolman, M. E. M., van Dorenmalen, K. M. A., Teske, G. J. D., Florquin, S., Schwede, F., et al. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013070679 · Cited by 40 · see citing works
Yu, Q., Si, R., Zhou, N., Zhang, H., Guo, W., Wang, H., & Gao, F. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0169-2 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles
Bonora, M., Wieckowski, M. R., Sinclair, D. A., Kroemer, G., Pinton, P., & Galluzzi, L. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0074-0 · Cited by 299 · see citing works
Subcellular Organization of the cAMP Signaling Pathway
Zaccolo, M., Zerio, A., & Lobo, M. J. (2020) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000086 · Cited by 271 · see citing works
Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development
Robichaux, W. G., & Cheng, X. (2018) · Physiological Reviews · doi:10.1152/physrev.00025.2017 · Cited by 208 · see citing works
CaMKII signaling in heart diseases: Emerging role in diabetic cardiomyopathy
Hegyi, B., Bers, D. M., & Bossuyt, J. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.01.001 · Cited by 143 · see citing works
Manzella, N., Santin, Y., Maggiorani, D., Martini, H., Douin‐Echinard, V., Passos, J. F., Lezoualc’h, F., Binda, C., Parini, A., & Mialet‐Perez, J. (2018) · Aging Cell · doi:10.1111/acel.12811 · Cited by 104 · see citing works
Self-citationSantin, Y., Fazal, L., Sainte–Marie, Y., Sicard, P., Maggiorani, D., Tortosa, F., Yücel, Y. Y., Teyssedre, L., Rouquette, J., Marcellin, M., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0470-y · Cited by 103 · see citing works
Self-citationCyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure
Kamel, R., Leroy, J., Vandecasteele, G., & Fischmeister, R. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00756-z · Cited by 100 · see citing works
Niu, X., Pu, S., Ling, C., Xu, J., Wang, J., Sun, S., Yao, Y., & Zhang, Z. (2020) · Cell Proliferation · doi:10.1111/cpr.12818 · Cited by 98 · see citing works
Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe?
Koju, N., Qin, Z., & Sheng, R. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00838-7 · Cited by 95 · see citing works
Perdijk, O., Butler, A., Macowan, M. G., Chatzis, R., Bulanda, E., Grant, R. D., Harris, N. L., Wypych, T. P., & Marsland, B. J. (2024) · Immunity · doi:10.1016/j.immuni.2024.06.010 · Cited by 92 · see citing works
Du, Y., Demillard, L. J., & Ren, J. T. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120106 · Cited by 78 · see citing works
Shaping mitochondrial dynamics: The role of cAMP signalling
Benedetto, G. D., Gerbino, A., & Lefkimmiatis, K. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.05.041 · Cited by 65 · see citing works
Brand, T., & Schindler, R. F. R. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.09.015 · Cited by 62 · see citing works
Pharmacological modulation of the CO2/HCO3−/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase
Wiggins, S. V., Steegborn, C., Levin, L. R., & Buck, J. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.05.008 · Cited by 59 · see citing works
Yang, H., Wei, X., Ding, C., Wang, C., Xu, B., Chen, S., Zha, B., Sun, Y., Zhu, H., Zhang, J., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9921982 · Cited by 51 · see citing works
Li, X., Liu, W., Jiang, G., Lian, J., Zhong, Y., Zhou, J., Li, H., Xu, X., Liu, Y., Cao, C., et al. (2024) · Advanced Science · doi:10.1002/advs.202307556 · Cited by 48 · see citing works
Laudette, M., Coluccia, A., Sainte–Marie, Y., Solari, A., Fazal, L., Sicard, P., Silvestri, R., Mialet‐Perez, J., Pons, S., Ghaleh, B., et al. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz076 · Cited by 46 · see citing works
Self-citationSarcoplasmic reticulum and calcium signaling in muscle cells: Homeostasis and disease
Bravo, R., Parra, V., Muñoz‐Córdova, F., Sánchez-Aguilera, P., Garrido, V., Contreras‐Ferrat, A. E., Chiong, M., & Lavandero, S. (2020) · International review of cytology · doi:10.1016/bs.ircmb.2019.12.007 · Cited by 46 · see citing works
Surinkaew, S., Aflaki, M., Takawale, A. R., Chen, Y., Qi, X., Gillis, M., Shi, Y., Tardif, J., Chattipakorn, N., & Nattel, S. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy173 · Cited by 43 · see citing works
The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology
Bouvet, M., Blondeau, J., & Lezoualc’h, F. (2019) · Cells · doi:10.3390/cells8121543 · Cited by 41 · see citing works
Self-citationHuang, Y., Wen, Q., Huang, J., Luo, M., Xiao, Y., Mo, R., & Wang, J. (2021) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-021-00267-8 · Cited by 39 · see citing works
Tronchère, H., Cinato, M., Timotin, A., Guitou, L., Villedieu, C., Thibault, H., Baetz, D., Payrastre, B., Valet, P., Parini, A., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607096 · Cited by 39 · see citing works
Epac Function and cAMP Scaffolds in the Heart and Lung
Laudette, M., Zuo, H., Lezoualc’h, F., & Schmidt, M. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5010009 · Cited by 37 · see citing works
Self-citationMusheshe, N., Oun, A., Sabogal-Guáqueta, A. M., Trombetta-Lima, M., Mitchel, S. C., Adžemović, A., Speek, O., Morra, F., van der Veen, C. H. T. J., Lezoualc’h, F., et al. (2022) · Antioxidants · doi:10.3390/antiox11020314 · Cited by 34 · see citing works
Self-citationZaccolo, M., & Kovanich, D. (2024) · Physiological Reviews · doi:10.1152/physrev.00013.2024 · Cited by 32 · see citing works
Macrophage Raptor Deficiency-Induced Lysosome Dysfunction Exacerbates Nonalcoholic Steatohepatitis
Liu, W., Ye, C., Cheng, Q., Zhang, X., Liu, Y., Li, Q., Huang, J., Liu, Y., Zou, Z., Wang, H., et al. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.09.011 · Cited by 30 · see citing works
Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity
Laudette, M., Sainte–Marie, Y., Cousin, G., Bergonnier, D., Belhabib, I., Brun, S., Formoso, K., Laib, L., Tortosa, F., Bergoglio, C., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04113-9 · Cited by 30 · see citing works
Self-citationTalmon, M., Rossi, S., Lim, D., Pollastro, F., Palattella, G., Ruffinatti, F. A., Marotta, P., Boldorini, R. L., Genazzani, A. A., & Fresu, L. G. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007763 · Cited by 30 · see citing works
Functional Significance of the Adcy10-Dependent Intracellular cAMP Compartments
Pozdniakova, S., & Ladilov, Y. V. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5020029 · Cited by 29 · see citing works
The Popeye Domain Containing Genes and Their Function as cAMP Effector Proteins in Striated Muscle
Brand, T. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5010018 · Cited by 28 · see citing works
Chang, J., Go, S., Gilglioni, E. H., Duijst, S., Panneman, D. M., Rodenburg, R. J., Li, H. L., Huang, H.-L., Levin, L. R., Buck, J., et al. (2021) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2020.148367 · Cited by 27 · see citing works
Peugnet, V., Chwastyniak, M., Mulder, P. G. H., Lancel, S., Bultot, L., Fourny, N., Renguet, E., Bugger, H., Beseme, O., Loyens, A., et al. (2022) · Antioxidants · doi:10.3390/antiox11040723 · Cited by 26 · see citing works
Jiang, L., He, H., Tang, Y., Li, J., Reilly, S. N., Xin, H., Li, Z., Cai, H., & Zhang, X. (2024) · Autophagy · doi:10.1080/15548627.2024.2367184 · Cited by 25 · see citing works
Guitart‐Mampel, M., Urquiza, P., Borges, J. I., Lymperopoulos, A., & Solesio, M. E. (2021) · Cells · doi:10.3390/cells10061552 · Cited by 24 · see citing works
Swan, A. H., Gruscheski, L., Boland, L. A., & Brand, T. (2019) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-019-09523-z · Cited by 23 · see citing works
Szanda, G., Wisniewski, É., Rajki, A., & Spät, A. (2018) · Journal of Cell Science · doi:10.1242/jcs.215178 · Cited by 22 · see citing works
Cardiac monoamine oxidases: at the heart of mitochondrial dysfunction
Mialet‐Perez, J., & Parini, A. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2251-4 · Cited by 22 · see citing works
Self-citationTargeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Hulsurkar, M. M., Lahiri, S. K., Karch, J. M., Wang, M. C., & Wehrens, X. H. T. (2022) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2022.2067479 · Cited by 21 · see citing works
Epac, a positive or negative signaling molecule in cardiovascular diseases
Tan, Y., Li, J., & Chen, H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112726 · Cited by 21 · see citing works
Cyclic AMP signaling in cardiac myocytes
Leroy, J., Vandecasteele, G., & Fischmeister, R. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2017.11.004 · Cited by 20 · see citing works
Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist
Shao, H., Mohamed, H., Boulton, S., Huang, J., Wang, P., Chen, H., Zhou, J., Luchowska-Stańska, U., Jentsch, N. G., Armstrong, A. L., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02151 · Cited by 20 · see citing works
The basics of mitochondrial cAMP signalling: Where, when, why
Benedetto, G. D., Lefkimmiatis, K., & Pozzan, T. (2020) · Cell Calcium · doi:10.1016/j.ceca.2020.102320 · Cited by 20 · see citing works
β2-adrenergic receptor regulates ER-mitochondria contacts
Lim, Y., Cho, I., Rennke, H. G., & Cho, G. (2021) · Scientific Reports · doi:10.1038/s41598-021-00801-w · Cited by 18 · see citing works
Epac: A Promising Therapeutic Target for Vascular Diseases: A Review
Pan, Y., Liu, J., Ren, J., Luo, Y., & Sun, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.929152 · Cited by 18 · see citing works
Membranes prime the RapGEF EPAC1 to transduce cAMP signaling
Cherfils, J., Sartre, C., Ferrandez, Y., Peurois, F., Ley, M., Zhang, W., Kryszke, M.-H., Courilleau, D., Fischmeister, R., Ambroise, Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39894-4 · Cited by 18 · see citing works
Yang, W., Xia, F., Mei, F. C., Shi, S., Robichaux, W. G., Lin, W., Zhang, W., Liu, H., & Cheng, X. (2023) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.64.11.34 · Cited by 18 · see citing works
Role of EPAC1 Signalosomes in Cell Fate: Friends or Foes?
Formoso, K., Lezoualc’h, F., & Mialet‐Perez, J. (2020) · Cells · doi:10.3390/cells9091954 · Cited by 18 · see citing works
Self-citationCyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Iannucci, L. F., D’Erchia, A. M., Picardi, E., Bettio, D., Conca, F., Surdo, N. C., Benedetto, G. D., Musso, D., Arrigoni, C., Lolicato, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41088-x · Cited by 17 · see citing works
In vitro and in vivo cardioprotective and metabolic efficacy of vitamin E TPGS/Apelin
Goto, P. L., Cinato, M., Merachli, F., Павлюк, Б. В., Jimenez, T., Marsal, D. J., Todua, N., Loi, H., Santin, Y., Cassel, S., et al. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.12.001 · Cited by 17 · see citing works
Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects
Aslam, M., & Ladilov, Y. V. (2021) · Cells · doi:10.3390/cells10020473 · Cited by 16 · see citing works
Zottola, A. C. P., Martín-Jiménez, R., Lavanco, G., Hamel-Côté, G., Ramon‐Duaso, C., Rodrigues, R. S., Mariani, Y., Khan, M., Drago, F., Jean, S., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02032-y · Cited by 15 · see citing works
Mo, Y., Wu, H., Zheng, X., Xu, L., Liu, L., & Liu, Z. (2021) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.22709 · Cited by 15 · see citing works
Халиулин, И. Г., Ascione, R., Маслов, Л. Н., Amal, H., & Suleiman, M. S. (2021) · Cells · doi:10.3390/cells10051223 · Cited by 15 · see citing works
Sympatho-adrenergic mechanisms in heart failure: new insights into pathophysiology
Du, X. (2021) · Medical Review · doi:10.1515/mr-2021-0007 · Cited by 15 · see citing works
The Role of POPDC Proteins in Cardiac Pacemaking and Conduction
Gruscheski, L., & Brand, T. (2021) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd8120160 · Cited by 15 · see citing works
GRKs and Epac1 Interaction in Cardiac Remodeling and Heart Failure
Laudette, M., Formoso, K., & Lezoualc’h, F. (2021) · Cells · doi:10.3390/cells10010154 · Cited by 14 · see citing works
Self-citationGreiser, M., Karbowski, M., Kaplan, A. D., Coleman, A. K., Verhoeven, N. A., Mannella, C. A., Lederer, W. J., & Boyman, L. (2023) · eLife · doi:10.7554/elife.84204 · Cited by 13 · see citing works
EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
Mazevet, M., Belhadef, A., Ribeiro, M., Daydé, D., Llach, A., Laudette, M., Belleville‐Rolland, T., Matéo, P., Gressette, M., Lefebvre, F., et al. (2023) · eLife · doi:10.7554/elife.83831 · Cited by 13 · see citing works
Self-citationSelective small-molecule EPAC activators
Luchowska-Stańska, U., Morgan, D., Yarwood, S. J., & Barker, G. (2019) · Biochemical Society Transactions · doi:10.1042/bst20190254 · Cited by 13 · see citing works
Visualization of Dynamic Mitochondrial Calcium Fluxes in Isolated Cardiomyocytes
Krstic, A. M., Power, A., & Ward, M. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.808798 · Cited by 13 · see citing works
Protective role of soluble adenylyl cyclase against reperfusion-induced injury of cardiac cells
Rinaldi, L., Pozdniakova, S., Jayarajan, V., Troidl, C., Abdallah, Y., Aslam, M., & Ladilov, Y. V. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.07.021 · Cited by 13 · see citing works
Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease
Demydenko, K., Ekhteraei‐Tousi, S., & Roderick, H. L. (2022) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2021.0319 · Cited by 12 · see citing works
Bitter taste receptor (TAS2R) 46 in human skeletal muscle: expression and activity
Talmon, M., Massara, E., Quaregna, M., Battisti, M. D., Boccafoschi, F., Lecchi, G., Puppo, F., Cajandab, M. A. B., Salamone, S., Bovio, E., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1205651 · Cited by 12 · see citing works
Sicard, P., Jouitteau, T., Andrade-Martins, T., Massad, A., de Araújo, G. R., David, H., Miquerol, L., Colson, P. H., & Richard, S. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00573.2018 · Cited by 12 · see citing works
Self-citationSorokin, O., Hause, F., Wedler, A., Alakhras, T., Bauchspiess, T., Dietrich, A., Günther, W. F., Guha, C., Obika, K. B., Kraft, J., et al. (2025) · APOPTOSIS · doi:10.1007/s10495-025-02161-6 · Cited by 11 · see citing works
Abbad, L., Détrait, M., Kavvadas, P., Bergonnier, D., Melis, L., Laudette, M., Migeon, T., Verpont, M., Lucas, A., Chatziantoniou, C., et al. (2024) · Kidney International · doi:10.1016/j.kint.2024.05.010 · Cited by 10 · see citing works
Self-citationForet, C., Figueroa, T., Bertin, A., Bessière, P., Lucas, A., Bergonnier, D., Wasniewski, M., Servat, A., Tessier, A., Lezoualc’h, F., et al. (2023) · Viruses · doi:10.3390/v15020319 · Cited by 10 · see citing works
Self-citationYang, M., Shu, W., Zhai, X., Yang, X., Zhou, H., Pan, B., Li, C., Lu, D., Cai, J., Zheng, S., et al. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05110-1 · Cited by 10 · see citing works
Martínez, E. M., Tusie, A. A. S., Darszon, A., Mayorga, L. S., Treviño, C. L., & Blas, G. A. D. (2021) · Andrology · doi:10.1111/andr.12989 · Cited by 10 · see citing works
Bizerra, P. F. V., Gilglioni, E. H., Li, H. L., Go, S., Elferink, R. P. J. O., Verhoeven, A. J., & Chang, J. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119585 · Cited by 9 · see citing works
Wang, W., Li, G., Ma, J., Fan, X., Lu, J., Sun, Q., Yao, J., & He, Q. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1346905 · Cited by 9 · see citing works
Aktories, K., Gierschik, P., zu Heringdorf, D. M., Schmidt, M., Schultz, G., & Wieland, T. (2019) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-019-01650-1 · Cited by 9 · see citing works
Mora, F. A. A., Musheshe, N., Arroyave-Ospina, J. C., Geng, Y., Soto, J. M., Rodrigo, J. A., Alieva, T., Buist‐Homan, M., Lezoualc’h, F., Cheng, X., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112072 · Cited by 9 · see citing works
Self-citationResearch progress on the role of CaMKII in heart disease.
Jiang, S., & Wang, W. (2020) · Europe PMC (PubMed Central) · Cited by 9 · see citing works
Liu, Q., Li, J., Li, Y.-X., Cheng, M. Y., Zhang, H., & Ma, B. (2024) · Biomolecules · doi:10.3390/biom14111430 · Cited by 6 · see citing works
Yao, B., Ma, J., Ran, Q., Chen, H., & He, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1483518 · Cited by 6 · see citing works
Cheng, H., Gao, Y., Han, W., Zhang, X., Zhang, X., Gao, R., Dang, W., Ma, Z., Liu, X., & Gao, Y. (2026) · Scientific Reports · doi:10.1038/s41598-025-30717-8 · Cited by 5 · see citing works
Mitochondrial cAMP and Ca2+ metabolism in adrenocortical cells
Spät, A., & Szanda, G. (2018) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2157-5 · Cited by 5 · see citing works
Boccella, N., Paolillo, R., & Perrino, C. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz188 · Cited by 5 · see citing works
Lecchi, G., Mocchetti, C., Tunesi, D., Berto, A., Balasubramanian, H. B., Biswas, S., Bagchi, A., Pollastro, F., Fresu, L. G., & Talmon, M. (2024) · Cells · doi:10.3390/cells13141204 · Cited by 4 · see citing works
Effect of zearalenone on the jejunum of weaned gilts through the Epac1/Rap1/JNK pathway
Liu, H., Ma, L., Fu, J., Ma, X., Gao, Y., Xie, Y., Yuan, X., Wang, Y., Yang, W., & Jiang, S. (2024) · Journal of Animal Science · doi:10.1093/jas/skae208 · Cited by 4 · see citing works
Ferri, G., Fernández, L. R., Mario, G. D., Musikant, D., Palermo, J. A., & Edreira, M. M. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1301862 · Cited by 4 · see citing works
Yang, W., Mei, F. C., Lin, W., Lee, J. E., Nie, S., Bley, C. J., Hoelz, A., & Cheng, X. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110279 · Cited by 3 · see citing works
Wang, Q., Xu, Y., Gao, Y., & Wang, Q. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.8953 · Cited by 3 · see citing works
Zhang, M., Liu, S., Wang, Y., Shan, S., & Cang, M. (2025) · Cells · doi:10.3390/cells14161234 · Cited by 2 · see citing works
Deciphering pro‐arrhythmogenic mechanisms of EPAC in human atrial cardiomyocytes
Boilève, A., Aize, M., Détrait, M., Brard, L., Leboyer, A., Dupont, P., Lebrun, A., Saplacan, V., Simard, C., Brette, F., et al. (2025) · The Journal of Physiology · doi:10.1113/jp288835 · Cited by 2 · see citing works
Self-citationThe cardiotropic properties of ZMEI-3 compound – a potential inhibitor of Epac proteins
Крыжановский, С. А., Мокров, Г. В., Цорин, И. Б., Ионова, Е. О., Вититнова, М. Б., Stolyaruk, V. N., Мирошкина, И. А., Сорокина, А. В., & Durnev, A. D. (2025) · Pharmacokinetics and Pharmacodynamics · doi:10.37489/2587-7836-2024-4-39-48 · Cited by 1 · see citing works
The role of mitochondria in the development of cardiovascular diseases
Deeb, H., & Perfilova, V. N. (2025) · I P Pavlov Russian Medical Biological Herald · doi:10.17816/pavlovj626203 · Cited by 1 · see citing works
Крыжановский, С. А., Никифорова, Т. Д., Вититнова, М. Б., & Дурнев, А. Д. (2020) · Human Physiology · doi:10.1134/s0362119720040076 · Cited by 1 · see citing works
La « dissection » moléculaire du remodelage cardiaque : perspectives thérapeutiques
Mialet‐Perez, J., & Lezoualc’h, F. (2017) · Archives des Maladies du Coeur et des Vaisseaux - Pratique · doi:10.1016/j.amcp.2017.04.005
Self-citationComparison of the Hypocalcemic Effects of Erythropoietin and U-74389G
Tsompos, C., Panoulis, C., Toutouzas, K., Triantafyllou, A., Zografos, C., Tsarea, K., Karamperi, M., & Papalois, A. E. (2019) · Clinical Research in Hematology · doi:10.33309/2639-8354.020201
Мокров, Г. В., Никифорова, Т. Д., & Крыжановский, С. А. (2020) · Pharmacokinetics and Pharmacodynamics · doi:10.37489/2587-7836-2019-4-3-17
Editor's evaluation: EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
Mangoni, A. A. (2023) · eLife · doi:10.7554/elife.83831.sa0
Rodrigues‐Ribeiro, L., Rezende-Ribeiro, J., Scalzo, S., Dias, M. L., Sanches, B., Eliezeck, M., de Jesus, I. C. G., Evaristo, J. A. M., Sampaio, K. H., Peruchetti, D. B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.27.586916
Reviews in Cardiovascular Pharmacology: 2023
(2025) · Frontiers research topics · doi:10.3389/978-2-8325-6052-5
Rôles et mécanismes d’action de la protéine Epac1 mitochondriale dans les pathologies cardiaques
Laudette, M. (2019) · theses.fr (ABES) · doi:10.70675/5a24dee4ze02cz4524za612zea3224b1ea32
Self-citation
- Authors
- Fazal, L., Laudette, M., Paula-Gomes, S., Pons, S., Conte, C., Tortosa, F., Sicard, P., Sainte-Marie, Y., Bisserier, M., Lairez, O., Lucas, A., Roy, J., Ghaleh, B., Fauconnier, J., Mialet-Perez, J., & Lezoualc’h, F.
- Affiliations
- Inserm (FR)
- From the Inserm, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (L.F., M.L., S.P.-G., C.C., F.T., P.S., Y.S.-M., M.B., O.L., A.L., J.M.-P., F.L.); Université de Toulouse, France (L.F., M.L., S.P.-G., C.C., F.T., P.S., Y.S.-M., M.B., O.L., A.L., J.M.-P., F.L.); Inserm, U955, Equipe 03, F-94000, Créteil, France (S.P., B.G.), and Inserm, UMR-1046 (J.R., J.F.); and UMR CNRS-9214, PHYMEDEX, Université de Montpellier, France (J.R., J.F.).
- Corresponding author
- Fazal, Loubina
- Laudette, Marion
- ORCID
- Venue
- Circulation Research
- Published
- 2017-02-17
- Volume
- 120
- Issue
- 4
- Pages
- 645-657
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2577171598
- Cited by
- 111
- References
- 42
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 13 · 2023: 11 · 2022: 9 · 2021: 16 · 2020: 12 · 2019: 15 · 2018: 20 · 2017: 5
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Fondation de France
- Université de Toulouse
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- Epac1, myocardial ischemia-reperfusion injury, cardiomyocyte apoptosis, mitochondrial calcium overload, VDAC1, GRP75, IP3R1, mitochondrial permeability transition pore, IDH2, CaMKII, NADPH production, hypoxia/reoxygenation, mitochondrial targeting sequence
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Heart Failure, Humans, Male, Mitochondria, Heart, Cell Death, Mice, Knockout, Guanine Nucleotide Exchange Factors, Membrane Microdomains, Myocytes, Cardiac, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
