43 results on '"Monceau V"'
Search Results
2. Supraventricular cardiac conduction system exposure in breast cancer patients treated with radiotherapy and association with heart and cardiac chambers doses
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Errahmani, M.Y., Locquet, M., Broggio, D., Spoor, D., Jimenez, G., Camilleri, J., Langendijk, J.A., Crijns, A.P.G., Bernier, M.O., Ferrières, J., Thariat, J., Boveda, S., Kirova, Y., Loap, P, Monceau, V., and Jacob, S.
- Published
- 2023
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3. Low to moderate dose 137 Cs (γ) radiation enhances M2 type macrophages function at short term associated with reduced inflammation at long term exposure in ApoE (-/-) mice
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Rey, N., primary, Ebrahimian, T., additional, Gloaguen, C ., additional, Kereselidze, D., additional, Elie, C., additional, Brizais, C., additional, Bachelot, F., additional, Riazi, G., additional, Monceau, V., additional, Demarquay, C ., additional, Zineddine, I. Garali, additional, Klokov, D ., additional, Lehoux, S., additional, and Ebrahimian, T.G., additional
- Published
- 2024
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4. Low to moderate dose 137Cs (γ) radiation promotes M2 type macrophage skewing and reduces atherosclerotic plaque CD68+ cell content in ApoE(−/−) mice.
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Rey, N., Ebrahimian, T., Gloaguen, C., Kereselidze, D., Christelle, E., Brizais, C., Bachelot, F., Riazi, G., Monceau, V., Demarquay, C., Zineddine, I. Garali, Klokov, D., Lehoux, S., and Ebrahimian, Teni G.
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DOSE-response relationship (Radiation) ,ATHEROSCLEROTIC plaque ,MACROPHAGES ,STAINS & staining (Microscopy) ,IONIZING radiation ,MUSCLE cells - Abstract
The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE
(−/−) mice to a single dose of 0, 0.05, 0.5 or 1 Gy of137 Cs (γ) administered at a 10.35 mGy min−1 dose rate and evaluated short-term (1–10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6CHigh and Ly6Low cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6CLow monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation. [ABSTRACT FROM AUTHOR]- Published
- 2024
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5. Effects of low doses of gamma-radiation on the development of cardiac pathologies and heart rhythm disorders in male C57Bl/6J mice
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Saliou, F., primary, Bachelot, F., additional, Suffee, N., additional, Mougenot, N., additional, Atassi, F., additional, Ménard, V., additional, Vetel, J., additional, Daydé, D., additional, Klokov, D., additional, Nadaud, S., additional, Morel, E., additional, and Monceau, V., additional
- Published
- 2023
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6. Association between cardiac radiation exposure and the risk of arrhythmia and conduction disorders in breast cancer patients treated with radiotherapy: A case-control study
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Errahmani, M.Y., primary, Locquet, M., additional, Spoor, D., additional, Jimenez, G., additional, Camilleri, J., additional, Bernier, M.O., additional, Broggio, D., additional, Monceau, V., additional, Ferrières, J., additional, Thariat, J., additional, Kirova, Y., additional, Loap, P., additional, Langendijk, J., additional, Crijns, A., additional, Boveda, S., additional, and Jacob, S., additional
- Published
- 2023
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7. Radiological and chemical exposures and risks of cancer in the Constances cohort (COREXCA)
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LAURENT, Olivier, Renaud, Philippe, Broggio, David, Blanchardon, Eric, Dreuil, Serge, Greau, Claire, Vignaud, Caroline, Ancelet, Sophie, Armant, Olivier, Bernier, Marie-Odile, Clero, Enora, Durand, Christelle, Ebrahimian Chiusa, Teni, Foucault, Anais, Goldberg, Marcel, Guerin, Sabine, Huet, Christelle, Lequy, Emeline, Métivier, Jean-Michel, Grison, Stephane, Ibanez, Chrystelle, Ielsch, Géraldine, Klokov, Dmitry, Monceau, V., Roy, Herve, guihenneuc, chantal, Leuraud, Klervi, Nathalie, Velly, Zins, Marie, Laboratoire d épidémiologie des rayonnements ionisants (IRSN/PSE-SANTE/SESANE/LEPID), Service de recherche sur les effets biologiques et Sanitaires des rayonnements ionisants (IRSN/PSE-SANTE/SESANE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Pôle Santé Environnement- Direction Environnement (IRSN/PSE-ENV), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Laboratoire d'évaluation de la dose interne (IRSN/PSE-SANTE/SDOS/LEDI), Service de dosimétrie (IRSN/PSE-SANTE/SDOS), Bureau d'expertise en radioprotection de la population (IRSN/PSE-ENV/SEREN/BERAP), Service d'expertise et d'étude en radioprotection des populations et de la radioactivité dans l'environnement (IRSN/PSE-ENV/SEREN), Unité d'expertise en radioprotection médicale (IRSN/PSE-SANTE/SER/UEM), Service d'études et d'expertise en radioprotection (IRSN/PSE-SANTE/SER), Bureau d'étude et d'expertise du radon (IRSN/PSE-ENV/SEREN/BERAD), Laboratoire d'écotoxicologie des radionucléides (IRSN/PSE-ENV/SRTE/LECO), Service de recherche sur les transferts et les effets des radionucléides sur les écosystèmes (IRSN/PSE-ENV/SRTE), Laboratoire de radiotoxicologie et radiobiologie expérimentale (IRSN/PSE-SANTE/SESANE/LRTOX), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut National de l'Environnement Industriel et des Risques (INERIS), Laboratoire de dosimétrie des rayonnements ionisants (IRSN/PSE-SANTE/SDOS/LDRI), Laboratoire d'étude et d'expertise sur la radioactivité de l'environnement (IRSN/PSE-ENV/SEREN/LEREN), Bureau d'analyse et de suivi des expositions professionnelles (IRSN/PSE-SANTE/SER/BASEP), Biostatistique, traitement et modélisation des données biologiques = Biostatistic, Biological Data treatment and Modelisation (BioSTM - URP_7537), Université Paris Cité (UPCité), Fondation de France (grant WB-2020-29711) French Agency for Food, Environmental and Occupational Health & Safety (ANSES, grant EST-21-188), European Radiation Protection Week, and European Project: 900009,RadoNorm
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[SDV]Life Sciences [q-bio] - Abstract
International audience
- Published
- 2022
8. P13-07 Uranium and kidney cancer: insights from genetically engineered mouse models in the UKCAN project
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Castro, L. De, Claude, O., Brisset, M., Gillot, C., Manoury, A., Sache, A., Voyer, F., Suhard, D., Monceau, V., Bouvier-Capely, C., Ibanez, C., and Guéguen, Y.
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- 2024
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9. Modulation pharmacologique des effets tardifs de l’irradiation
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Bourgier, C., Monceau, V., Bourhis, J., Deutsch, É., and Vozenin, M.-C.
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- 2011
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10. Radiological component of the Exposome, multiple exposures, risks of cancer and other chronic diseases in the Constances cohort (CORALE)
- Author
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LAURENT, Olivier, Renaud, Philippe, Dreuil, Serge, Greau, Claire, Vignaud, Caroline, Ancelet, Sophie, Armant, Olivier, Bernier, Marie-Odile, Clero, Enora, Durand, Christelle, Ebrahimian Chiusa, Teni, Goldberg, Marcel, Lequy, Emeline, Grison, Stephane, Ibanez, Chrystelle, Ielsch, Géraldine, Klokov, Dmitry, Monceau, V., Roy, Herve, Guihenneuc, Chantal, Leuraud, Klervi, Zins., Marie, Laboratoire d épidémiologie des rayonnements ionisants (IRSN/PSE-SANTE/SESANE/LEPID), Service de recherche sur les effets biologiques et Sanitaires des rayonnements ionisants (IRSN/PSE-SANTE/SESANE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Pôle Santé Environnement- Direction Environnement (IRSN/PSE-ENV), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Unité d'expertise en radioprotection médicale (IRSN/PSE-SANTE/SER/UEM), Service d'études et d'expertise en radioprotection (IRSN/PSE-SANTE/SER), Bureau d'étude et d'expertise du radon (IRSN/PSE-ENV/SEREN/BERAD), Service d'expertise et d'étude en radioprotection des populations et de la radioactivité dans l'environnement (IRSN/PSE-ENV/SEREN), Laboratoire d'écotoxicologie des radionucléides (IRSN/PSE-ENV/SRTE/LECO), Service de recherche sur les transferts et les effets des radionucléides sur les écosystèmes (IRSN/PSE-ENV/SRTE), Laboratoire de radiotoxicologie et radiobiologie expérimentale (IRSN/PSE-SANTE/SESANE/LRTOX), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Bureau d'analyse et de suivi des expositions professionnelles (IRSN/PSE-SANTE/SER/BASEP), Biostatistique, traitement et modélisation des données biologiques = Biostatistic, Biological Data treatment and Modelisation (BioSTM - URP_7537), Université Paris Cité (UPCité), Fondation de France, Radonorm, and European Project: 900009,RadoNorm
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[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie - Abstract
International audience; ContextThe whole population is exposed throughout its life to ionizing radiation (IR) at varying levels, via multiple natural and artificial sources, whether in the context of the residential environment, various activities (professional or other such as air travel) or for medical reasons (diagnostic or therapeutic procedures). The carcinogenic effects of IR are well documented at dose levels of 100 milliGrays (mGy) or higher. There is still controversy about the shape of the relationships between exposure and cancer risks at lower doses, called “low doses”. In addition, quantification of the effects of multi-exposure to IR and other cancer risk factors is poorly documented, with the exception of the interaction between tobacco and radon on lung cancer risk. Similarly, the relationships between exposures to IR at different stages of life (e.g., during childhood, puberty, etc.) and late health effects remain poorly characterized. Potential associations between low doses of IR and non-cancer chronic diseases also require better documentation. ObjectivesThe first objective of the CORALE project is to carry out the broadest possible reconstruction of doses of IR from environmental sources (radon, terrestrial and cosmic radiation, food, nuclear installations and other artificial sources), medical (diagnostic and therapeutic procedures) and occupational (nuclear workers but also other industries using radioactive sources, health professionals… ) received by participants in the Constances cohort since birth, following the logic of the exposome concept (for its radiological component). The second objective will be to estimate the risks of cancers and other chronic diseases potentially associated with the cumulative doses received (from several sources of IR and over time) taking into account the potential influence of the context of multi-exposures to other risk factors.MethodsIn order to reconstruct the annual doses due to radioactivity of natural and artificial origin received by each member of the Constances cohort since their birth, a large number of sources of radioactivity must be considered. Reconstructions related to environmental, medical and occupational exposures will be performed by different units of the IRSN in collaboration with the Constances cohort team. To do this, a questionnaire will be sent to cohort members who have already provided their residential histories. The statistical analyses (e.g., Cox models with time-dependent covariates) will be carried out at the IRSN epidemiology laboratory and will benefit from the expertise of radiobiologists, supporting the exploration of specific hypotheses and interpretations. The use of innovative regression methods on exposure profiles will be explored in collaboration with the University of Paris.PerspectivesCORALE is part of a broader long-term research programme, which will include the effects of other multi-exposures (e.g., IR and other environmental exposures) and the study of risk and exposure biomarkers through the Constances biobank, further complementing the application of the exposome concept through the study of within-body regulations following exposures. This program will help improve the characterization of the exposome and its relation with chronic diseases in the Constances cohort.
- Published
- 2021
11. Annexin 5 overexpression increased articular chondrocyte apoptosis induced by basic calcium phosphate crystals
- Author
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Ea, H K, Monceau, V, Camors, E, Cohen-Solal, M, Charlemagne, D, and Lioté, F
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- 2008
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12. PO-0955: Co-treatment of MSC and vascular permeability inhibitor reduces radiation side effects on the colon
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Monceau, V., primary, Demarquay, C., additional, Accarie, A., additional, Moussa, L., additional, Doix, B., additional, Benderitter, M., additional, Sémont, A., additional, and Mathieu, N., additional
- Published
- 2017
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13. Moderated Poster session - Vascular26Identification of CMTM3 as a new pro-angiogenic factor essential for vessel stabilization27Regulation of pulmonary vascular PW1+ progenitor cells recruitment during early chronic hypoxia-induced vessel neomuscularization28Impaired interleukin-10 production in response to CpG and depletion of the regulatory CD19+CD24hiCD38hi B cell compartment in patients with coronary atherosclerosis29Inflammatory effects of serum amyloid A via TLR2 and TLR4 in vascular cells30Collagen cross-linking enzymes are involved in vascular smooth muscle cells calcification31miR-504 inhibits venous smooth muscle cell proliferation and migration by targeting LAMTOR132Diaphenous related formin 2 (DRF2) is essential for KLF2-induced resistance of endothelial cells to flow forces.33Inhibition of TGfb axis and renin-angiotensin system in human ascending aorta aneurysms
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Chrifi, I, primary, Dierick, F, primary, Dumitriu, I E, primary, Schuchardt, M, primary, Jover, E, primary, Yan, Z, primary, Fontijn, R D, primary, Borges, L, primary, Brandt, MM, additional, Cheng, C, additional, Duncker, DJGM, additional, Monceau, V, additional, Hoareau, B, additional, Mougenot, N, additional, Marazzi, G, additional, Sassoon, D, additional, Hulot, JS, additional, Soubrier, F, additional, Nadaud, S, additional, Baruah, P, additional, Dinkla, S, additional, Bullenkamp, J, additional, Kaski, JC, additional, Tu, Y, additional, Pruefer, N, additional, Toelle, M, additional, Chebli, S, additional, Zidek, W, additional, Van Der Giet, M, additional, Silvente, A, additional, Marin, F, additional, Rodriguez, C, additional, Martinez-Gonzalez, J, additional, Puche, CM, additional, Valdes, M, additional, Hernandez Romero, D, additional, Tan, J, additional, Yang, L, additional, Valent, ET, additional, Leyen, TA, additional, Szulcek, R, additional, Baggen, JM, additional, Geerts, D, additional, Van Nieuw Amerongen, GP, additional, Horrevoets, AJG, additional, Alvarenga, LAA, additional, Falcao, RSP, additional, Dias, RR, additional, Lacchini, S, additional, Gutierrez, PS, additional, and Michel, JB, additional
- Published
- 2016
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14. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity
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Monceau, V., Pasinetti, N, Schupp, C., Pouzoulet, F., and Vozenin, P. OPOLON AND M. C.
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- 2010
15. 155: Cardiac toxicity induced by radiotherapy. Role of the GEF, Epac, in hypertrophy and amyloidosis but not in fibrosis
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Petit, B., primary, Azria, D., additional, Bourgier, C., additional, Bourhis, J., additional, Bridier, A., additional, Dörr, W., additional, Escoudet, B., additional, Fenoglietto, P., additional, Gomez, A.M., additional, Gourgou, S., additional, Llach, A., additional, Monceau, V., additional, Morel, E., additional, Strup-Perrot, C., additional, To, V., additional, and Vozenin, M.C., additional
- Published
- 2014
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16. La surexpression de l'annexine V augmente l'apoptose des chondrocytes articulaires induite par les cristaux de phosphate de calcium basique et le TNFα
- Author
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Ea, H.-K., primary, Monceau, V., additional, Cohen-Solal, M., additional, Camors, E., additional, Uzan, B., additional, Rey, C., additional, Charlemagne, D., additional, and Lioté, F., additional
- Published
- 2006
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17. Annexins and Ca handling in the heart
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CAMORS, E, primary, MONCEAU, V, additional, and CHARLEMAGNE, D, additional
- Published
- 2005
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18. Externalization of endogenous annexin A5 participates in apoptosis of rat cardiomyocytes
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MONCEAU, V, primary, BELIKOVA, Y, additional, KRATASSIOUK, G, additional, CHARUE, D, additional, CAMORS, E, additional, COMMUNAL, C, additional, TROUVE, P, additional, RUSSOMARIE, F, additional, and CHARLEMAGNE, D, additional
- Published
- 2004
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19. X-ray Radiotherapy Impacts Cardiac Dysfunction by Modulating the Sympathetic Nervous System and Calcium Transients.
- Author
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Feat-Vetel J, Suffee N, Bachelot F, Dos Santos M, Mougenot N, Delage E, Saliou F, Martin S, Brunet I, Sicard P, and Monceau V
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- Animals, Mice, Female, X-Rays, Heart radiation effects, Heart physiopathology, Atrial Remodeling radiation effects, Sympathetic Nervous System radiation effects, Sympathetic Nervous System metabolism, Mice, Inbred C57BL, Calcium metabolism
- Abstract
Recent epidemiological studies have shown that patients with right-sided breast cancer (RBC) treated with X-ray irradiation (IR) are more susceptible to developing cardiovascular diseases, such as arrhythmias, atrial fibrillation, and conduction disturbances after radiotherapy (RT). Our aim was to investigate the mechanisms induced by low to moderate doses of IR and to evaluate changes in the cardiac sympathetic nervous system (CSNS), atrial remodeling, and calcium homeostasis involved in cardiac rhythm. To mimic the RT of the RBC, female C57Bl/6J mice were exposed to X-ray doses ranging from 0.25 to 2 Gy targeting 40% of the top of the heart. At 60 weeks after RI, Doppler ultrasound showed a significant reduction in myocardial strain, ejection fraction, and atrial function, with a significant accumulation of fibrosis in the epicardial layer and apoptosis at 0.5 mGy. Calcium transient protein expression levels, such as RYR2, NAK, Kir2.1, and SERCA2a, increased in the atrium only at 0.5 Gy and 2 Gy at 24 h, and persisted over time. Interestingly, 3D imaging of the cleaned hearts showed an early reduction of CSNS spines and dendrites in the ventricles and a late reorientation of nerve fibers, combined with a decrease in SEMA3a expression levels. Our results showed that local heart IR from 0.25 Gy induced late cardiac and atrial dysfunction and fibrosis development. After IR, ventricular CSNS and calcium transient protein expression levels were rearranged, which affected cardiac contractility. The results are very promising in terms of identifying pro-arrhythmic mechanisms and preventing arrhythmias during RT treatment in patients with RBC.
- Published
- 2024
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20. Effects of moderate doses of ionizing radiation on experimental abdominal aortic aneurysm.
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Riazi G, Brizais C, Garali I, Al-Rifai R, Quelquejay H, Monceau V, Vares G, Ould-Boukhitine L, Aubeleau D, Gilain F, Gloaguen C, Dos Santos M, Ait-Oufella H, and Ebrahimian T
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- Animals, Mice, Male, Disease Models, Animal, Interleukin-10 metabolism, Interleukin-10 genetics, Collagen metabolism, Cell Proliferation radiation effects, Aortic Aneurysm, Abdominal pathology, Aortic Aneurysm, Abdominal metabolism, Aortic Aneurysm, Abdominal etiology, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular radiation effects, Muscle, Smooth, Vascular pathology, Radiation, Ionizing, Angiotensin II pharmacology, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle radiation effects, Myocytes, Smooth Muscle pathology
- Abstract
Background: Exposure to ionizing radiation has been linked to cardiovascular diseases. However, the impact of moderate doses of radiation on abdominal aortic aneurysm (AAA) remains unknown., Methods: Angiotensin II-infused Apoe-/- mice were irradiated (acute, 1 Gray) either 3 days before (Day-3) or 1 day after (Day+1) pomp implantation. Isolated primary aortic vascular smooth muscle cells (VSMCs) were irradiated (acute 1 Gray) for mechanistic studies and functional testing in vitro., Results: Day-3 and Day+1 irradiation resulted in a significant reduction in aorta dilation (Control: 1.39+/-0.12; Day-3: 1.12+/-0.11; Day+1: 1.15+/-0.08 mm, P<0.001) and AAA incidence (Control: 81.0%; Day-3: 33.3%, Day+1: 53.3%) compared to the non-irradiated group. Day-3 and Day+1 irradiation led to an increase in collagen content in the adventitia (Thickness control: 23.64+/-2.9; Day-3: 54.39+/-15.5; Day+1 37.55+/-10.8 mm, P = 0.006). However, the underlying protective mechanisms were different between Day-3 and Day+1 groups. Irradiation before Angiotensin II (AngII) infusion mainly modulated vascular smooth muscle cell (VSMC) phenotype with a decrease in contractile profile and enhanced proliferative and migratory activity. Irradiation after AngII infusion led to an increase in macrophage content with a local anti-inflammatory phenotype characterized by the upregulation of M2-like gene and IL-10 expression., Conclusion: Moderate doses of ionizing radiation mitigate AAA either through VSCM phenotype or inflammation modulation, depending on the time of irradiation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Riazi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
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21. Exposure to tungsten particles via inhalation triggers early toxicity marker expression in the rat brain.
- Author
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Macé L, Brizais C, Bachelot F, Manoury A, Thomé S, Gloaguen C, Garali I, Magneron V, Monceau V, Sache A, Voyer F, Elie C, Roy L, Gensdarmes F, Klokov D, Block ML, and Ibanez C
- Subjects
- Animals, Male, Rats, Biomarkers metabolism, Microglia drug effects, Microglia metabolism, Neurons drug effects, Neurons metabolism, Lung drug effects, Lung metabolism, Olfactory Bulb drug effects, Olfactory Bulb metabolism, Apoptosis drug effects, Oxidative Stress drug effects, Tungsten toxicity, Inhalation Exposure adverse effects, Brain drug effects, Brain metabolism, Rats, Wistar
- Abstract
Objective: Our work is focused on tungsten, considered as an emerging contaminant. Its environmental dispersion is partly due to mining and military activities. Exposure scenario can also be occupational, in areas such as the hard metal industry and specific nuclear facilities. Our study investigated the cerebral effects induced by the inhalation of tungsten particles., Methods: Inhalation exposure campaigns were carried out at two different concentrations (5 and 80 mg/m
3 ) in single and repeated modes (4 consecutive days) in adult rats within a nose-only inhalation chamber. Processes involved in brain toxicity were investigated 24 h after exposure., Results and Discussion: Site-specific effects in terms of neuroanatomy and concentration-dependent changes in specific cellular actors were observed. Results obtained in the olfactory bulb suggest a potential early effect on the survival of microglial cells. Depending on the mode of exposure, these cells showed a decrease in density accompanied by an increase in an apoptotic marker. An abnormal phenotype of the nuclei of mature neurons, suggesting neuronal suffering, was also observed in the frontal cortex, and can be linked to the involvement of oxidative stress. The differential effects observed according to exposure patterns could involve two components: local (brain-specific) and/or systemic. Indeed, tungsten, in addition to being found in the lungs and kidneys, was present in the brain of animals exposed to the high concentration., Conclusion: Our data question the perceived innocuity of tungsten relative to other metals and raise hypotheses regarding possible adaptive or neurotoxic mechanisms that could ultimately alter neuronal integrity.- Published
- 2024
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22. T-cell dysregulation and inflammatory process in Gcn2 ( Eif2ak4 -/- )-deficient rats in basal and stress conditions.
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Bignard J, Atassi F, Claude O, Ghigna MR, Mougenot N, Abdoulkarim BS, Deknuydt F, Gestin A, Monceau V, Montani D, Nadaud S, Soubrier F, and Perros F
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- Animals, Rats, Lung metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, RNA, Messenger, Hypertension, Pulmonary, Pulmonary Veno-Occlusive Disease genetics
- Abstract
Hereditary pulmonary veno-occlusive disease (hPVOD) is a severe form of autosomal recessive pulmonary hypertension and is due to biallelic loss of function of the EIF2AK4 gene (alias GCN 2) coding for GCN2. GCN2 is a stress kinase that belongs to the integrated stress response pathway (ISR). Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease. We submitted these rats to amino acid deprivation to document the molecular and cellular response of the lungs and to identify phenotypic changes that could be involved in PVOD pathophysiology. Gcn2
-/- rat lungs were analyzed under basal conditions and 3 days after a single administration of PEG-asparaginase (ASNase). Lung mRNAs were analyzed by RNAseq and single-cell RNAseq (scRNA-seq), flow cytometry, tissue imaging, and Western blots. The ISR was not activated after ASNase treatment in Gcn2-/- rat lungs, and apoptosis was increased. Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area. Under basal conditions, scRNA-seq analysis of Gcn2-/- rat lungs revealed increases in two T-cell populations, a LAG3+ T-cell population and a proliferative T-cell population. Following ASNase administration, we observed an increase in calprotectin expression involved in TLR pathway activation and neutrophil infiltration. In conclusion, under basal and asparagine and glutamine deprivation induced by asparaginase administration, Gcn2-/- rats display molecular and cellular signatures in the lungs that may indicate a role for Gcn2 in immune homeostasis and provide further clues to the mechanisms of hPVOD development.- Published
- 2023
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23. Renal toxicity and biokinetics models after repeated uranium instillation.
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De Castro L, Manoury A, Claude O, Simoneau B, Monceau V, Suhard D, Elie C, Magneron V, Roy L, Bouvier-Capely C, Ibanez C, Davesne E, and Guéguen Y
- Subjects
- Mice, Animals, Mice, Inbred C57BL, Kidney pathology, Feces, Uranium toxicity, Body Fluids
- Abstract
During nuclear fuel processing, workers can potentially be exposed to repeated inhalations of uranium compounds. Uranium nephrotoxicity is well documented after acute uranium intake, but it is controversial after long-term or protracted exposure. This study aims to analyze the nephrotoxicity threshold after repeated uranium exposure through upper airways and to investigate the resulting uranium biokinetics in comparison to reference models. Mice (C57BL/6J) were exposed to uranyl nitrate (0.03-3 mg/kg/day) via intranasal instillation four times a week for two weeks. Concentrations of uranium in urines and tissues were measured at regular time points (from day 1 to 91 post-exposure). At each exposure level, the amount of uranium retained in organs/tissues (kidney, lung, bone, nasal compartment, carcass) and excreta (urine, feces) reflected the two consecutive weeks of instillation except for renal uranium retention for the highest uranium dose. Nephrotoxicity biomarkers, KIM-1, clusterin and osteopontin, are induced from day 4 to day 21 and associated with changes in renal function (arterial fluxes) measured using non-invasive functional imaging (Doppler-ultrasonography) and confirmed by renal histopathological analysis. These results suggest that specific biokinetic models should be developed to consider altered uranium excretion and retention in kidney due to nephrotoxicity. The threshold is between 0.25 and 1 mg/kg/day after repeated exposure to uranium via upper airways., (© 2023. The Author(s).)
- Published
- 2023
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24. Dosimetric evaluation of the benefit of deep inspiration breath hold (DIBH) for locoregional irradiation of right breast cancer with volumetric modulated arctherapy (VMAT).
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Loap P, Vu-Bezin J, Monceau V, Jacob S, Fourquet A, and Kirova Y
- Subjects
- Humans, Female, Breath Holding, Radiotherapy Planning, Computer-Assisted methods, Radiotherapy Dosage, Heart radiation effects, Organs at Risk radiation effects, Breast Neoplasms radiotherapy, Radiotherapy, Intensity-Modulated methods, Unilateral Breast Neoplasms radiotherapy
- Abstract
Introduction: Right-lateralized cardiac substructures can be substantially exposed during right breast cancer (R-BC) radiotherapy. The cardiac benefit of deep inspiration breath hold (DIBH) is established in combination with volumetric modulated arctherapy (VMAT) for left breast cancer with regional node irradiation but is unknown for R-BC. This study evaluated the dosimetric benefit of DIBH for locoregional irradiation of R-BC with VMAT., Material and Methods: All patients treated for R-BC with adjuvant locoregional DIBH-VMAT in the Department of Radiation Oncology of the Institut Curie (Paris, France) until December 2022 were included, corresponding to 15 patients. FB- and DIBH-VMAT plans were compared both for a normofractionated regimen (50 Gy/25fx) used for treatment and a replanned hypofractionated regimen (40 Gy/15fx). Dose to the heart, cardiac substructures (sinoatrial node (SAN), atrio-ventricular node (AVN), right coronary artery, left anterior descending coronary artery, left ventricle), ipsilateral lung and liver were retrieved and compared., Results: Mean heart dose (MHD) was 3.33 Gy with FB vs. 3.10 Gy with DIBH on normofractionated plans ( p = 0.489), and 2.58 Gy with FB vs. 2.41 Gy with DIBH on hypofractionated plan ( p = 0.489). The benefit of DIBH was not significant for any cardiac substructure. The most exposed cardiac substructure were the SAN (mean dose of 6.62 Gy for FB- and 5.64 Gy for DIBH-VMAT on normofractionated plans) and the RCA (mean dose of 4.21 Gy for FB- and 4.06 Gy for DIBH-VMAT on normofractionated plans). The maximum benefit was observed for the RCA with a median individual dose reduction of 0.84 Gy on normofractionated plans ( p = 0.599). No significant dosimetric difference were observed for right lung. Liver mean dose was significantly lower with DIBH with median values decreasing from 2.54 Gy to 0.87 Gy ( p = 0.01)., Conclusion: Adding DIBH to efficient cardiac-sparing radiotherapy techniques, such as VMAT, is not justified in the general case for locoregional R-BC irradiation. Specific R-BC patient subpopulations who could benefit from additional DIBH combination with locoregional VMAT are yet to be identified.
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- 2023
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25. Editorial: Cardiotoxicity induced by radiotherapy and/or chemotherapy after cancer treatment.
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Boerma M, Azimzadeh O, Pasinetti N, and Monceau V
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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26. Supraventricular cardiac conduction system exposure in breast cancer patients treated with radiotherapy and association with heart and cardiac chambers doses.
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Errahmani MY, Locquet M, Broggio D, Spoor D, Jimenez G, Camilleri J, Langendijk JA, Crijns APG, Bernier MO, Ferrières J, Thariat J, Boveda S, Kirova Y, Loap P, Monceau V, and Jacob S
- Abstract
Purpose: To assess sinoatrial node (SAN) and atrioventricular node (AVN) doses for breast cancer (BC) patients treated with 3D-CRT and evaluate whether "large" cardiac structures (whole heart and four cardiac chambers) would be relevant surrogates., Material and Methods: This single center study was based on 116 BCE patients (56 left-sided, 60 right-sided) treated with 3D-CRT without respiratory gating strategies and few IMN irradiations from 2009 to 2013. The heart, the left and right ventricles (LV, RV), the left and right atria (LA, RA) were contoured using multi-atlases for auto-segmentation. The SAN and the AVN were manually delineated using a specific atlas. Based on regression analysis, the coefficients of determination (R
2 ) were estimated to evaluate whether "large" cardiac structures were relevant surrogates (R2 > 0.70) of SAN and AVN doses., Results: For left-sided BC, mean doses were: 3.60 ± 2.28 Gy for heart, 0.47 ± 0.24 Gy for SAN and 0.74 ± 0.29 Gy for AVN. For right-sided BC, mean heart dose was 0.60 ± 0.25 Gy, mean SAN dose was 1.57 ± 0.63 Gy (>85 % of patients with SAN doses > 1 Gy) and mean AVN dose was 0.51 ± 0.14 Gy. Among all "large" cardiac structures, RA appeared as the best surrogate for SAN doses (R2 > 0.80). Regarding AVN doses, the RA may also be an interesting surrogate for left-sided BC (R2 = 0.78), but none of "large" cardiac structures appeared as relevant surrogates among right-sided BC (all R2 < 0.70), except the LA for patients with IMN (R2 = 0.83)., Conclusions: In BC patients treated 10 years ago with 3D-CRT, SAN and AVN exposure was moderate but could exceed 1 Gy to the SAN in many right-sided patients with no IMN-inclusion. The RA appeared as an interesting surrogate for SAN exposure. Specific conduction nodes delineation remains necessary by using modern radiotherapy techniques., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)- Published
- 2022
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27. Association Between Cardiac Radiation Exposure and the Risk of Arrhythmia in Breast Cancer Patients Treated With Radiotherapy: A Case-Control Study.
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Errahmani MY, Locquet M, Spoor D, Jimenez G, Camilleri J, Bernier MO, Broggio D, Monceau V, Ferrières J, Thariat J, Boveda S, Kirova Y, Loap P, Langendijk JA, Crijns A, and Jacob S
- Abstract
Background: Previous studies suggested that radiation therapy (RT) for breast cancer (BC) can induce cardiac arrhythmias and conduction disorders. However, the association with mean heart dose and specific cardiac substructures doses was less studied., Materials and Methods: We conducted a nested case-control study based on French BC patients, enrolled in the European MEDIRAD-BRACE study (https://clinicaltrials.gov, Identifier: NCT03211442), who underwent three-dimensional conformal radiation therapy (3D-CRT) between 2009 and 2013 and were retrospectively followed until 2019. Cases were incident cases of cardiac arrhythmia. Controls without arrhythmia were selected with propensity-scored matching by age, duration of follow-up, chemotherapy, hypertension, and diabetes (ratio 1:4 or 5). Doses to the whole heart (WH), left and right atria (LA and RA), and left and right ventricles (LV and RV) were obtained after delineation with multi-atlas-based automatic segmentation., Results: The study included 116 patients (21 cases and 95 controls). Mean age at RT was 64 ± 10 years, mean follow-up was 7.0 ± 1.3 years, and mean interval from RT to arrhythmia was 4.3 ± 2.1 years. None of the results on association between arrhythmia and cardiac doses reached statistical significance. However, the proportion of right-sided BC was higher among patients with arrhythmia than among controls (57% vs. 51%, OR = 1.18, p = 0.73). Neither mean WH dose, nor LV, RV, and LA doses were associated with an increased risk of arrhythmia (OR = 1.00, p > 0.90). In contrast, the RA dose was slightly higher for cases compared to controls [interquartile range (0.61-1.46 Gy) vs. (0.49-1.31 Gy), p = 0.44], and a non-significant trend toward a potentially higher risk of arrhythmia with increasing RA dose was observed (OR = 1.19, p = 0.60). Subanalysis according to BC laterality showed that the association with RA dose was reinforced specifically for left-sided BC (OR = 1.76, p = 0.75), while for right-sided BC, the ratio of mean RA/WH doses may better predict arrhythmia (OR = 2.39, p = 0.35)., Conclusion: Despite non-significant results, our exploratory investigation on BC patients treated with RT is the first study to suggest that right-sided BC patients and the right atrium irradiation may require special attention regarding the risk of cardiac arrhythmia and conduction disorders. Further studies are needed to expand on this topic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MB is currently organizing a Research Topic with the author VM., (Copyright © 2022 Errahmani, Locquet, Spoor, Jimenez, Camilleri, Bernier, Broggio, Monceau, Ferrières, Thariat, Boveda, Kirova, Loap, Langendijk, Crijns and Jacob.)
- Published
- 2022
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28. Platelet-Derived Growth Factor Receptor Type α Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension.
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Solinc J, Raimbault-Machado J, Dierick F, El Bernoussi L, Tu L, Thuillet R, Mougenot N, Hoareau-Coudert B, Monceau V, Pavoine C, Atassi F, Sassoon D, Marazzi G, Harvey RP, Schofield P, Christ D, Humbert M, Guignabert C, Soubrier F, and Nadaud S
- Subjects
- Animals, Cell Proliferation, Cells, Cultured, Humans, Hypoxia, Lung, Male, Mice, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Pulmonary Artery, Vascular Remodeling, Hypertension, Pulmonary metabolism, Receptor, Platelet-Derived Growth Factor alpha metabolism
- Abstract
Background Platelet-derived growth factor is a major regulator of the vascular remodeling associated with pulmonary arterial hypertension. We previously showed that protein widely 1 (PW1
+ ) vascular progenitor cells participate in early vessel neomuscularization during experimental pulmonary hypertension (PH) and we addressed the role of the platelet-derived growth factor receptor type α (PDGFRα) pathway in progenitor cell-dependent vascular remodeling and in PH development. Methods and Results Remodeled pulmonary arteries from patients with idiopathic pulmonary arterial hypertension showed an increased number of perivascular and vascular PW1+ cells expressing PDGFRα. PW1nLacZ reporter mice were used to follow the fate of pulmonary PW1+ progenitor cells in a model of chronic hypoxia-induced PH development. Under chronic hypoxia, PDGFRα inhibition prevented the increase in PW1+ progenitor cell proliferation and differentiation into vascular smooth muscle cells and reduced pulmonary vessel neomuscularization, but did not prevent an increased right ventricular systolic pressure or the development of right ventricular hypertrophy. Conversely, constitutive PDGFRα activation led to neomuscularization via PW1+ progenitor cell differentiation into new smooth muscle cells and to PH development in male mice without fibrosis. In vitro, PW1+ progenitor cell proliferation, but not differentiation, was dependent on PDGFRα activity. Conclusions These results demonstrate a major role of PDGFRα signaling in progenitor cell-dependent lung vessel neomuscularization and vascular remodeling contributing to PH development, including in idiopathic pulmonary arterial hypertension patients. Our findings suggest that PDGFRα blockers may offer a therapeutic add-on strategy to combine with current pulmonary arterial hypertension treatments to reduce vascular remodeling. Furthermore, our study highlights constitutive PDGFRα activation as a novel experimental PH model.- Published
- 2022
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29. Sex-Specific Differences in Toxicity Following Systemic Paclitaxel Treatment and Localized Cardiac Radiotherapy.
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Chmielewski-Stivers N, Petit B, Ollivier J, Monceau V, Tsoutsou P, Quintela Pousa A, Lin X, Limoli C, and Vozenin MC
- Abstract
The impact of sex in the development of long-term toxicities affecting the quality of life of cancer survivors has not been investigated experimentally. To address this issue, a series of neurologic and cardiologic endpoints were used to investigate sex-based differences triggered by paclitaxel treatment and radiotherapy exposure. Male and female wild-type (WT) mice were treated with paclitaxel (150 and 300 mg/kg) administered weekly over 6 weeks or exposed to 19 Gy cardiac irradiation. Cohorts were analyzed for behavioral and neurobiologic endpoints to assess systemic toxicity of paclitaxel or cardiovascular endpoints to assess radiotherapy toxicity. Interestingly, female WT mice exhibited enhanced tolerance compared to male WT mice regardless of the treatment regimen. To provide insight into the possible sex-specific protective mechanisms, rhoB- deficient animals and elderly mice (22 months) were used with a focus on the possible contribution of sex hormones, including estrogen. In females, RhoB deficiency and advanced age had no impact on neurocognitive impairment induced by paclitaxel but enhanced cardiac sensitivity to radiotherapy. Conversely, rhoB- deficiency protected males from radiation toxicity. In sum, RhoB was identified as a molecular determinant driving estrogen-dependent cardioprotection in female mice, whereas neuroprotection was not sex hormone dependent. To our knowledge, this study revealed for the first time sex- and organ-specific responses to paclitaxel and radiotherapy.
- Published
- 2021
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30. Expert consultation is vital for adverse outcome pathway development: a case example of cardiovascular effects of ionizing radiation.
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Chauhan V, Hamada N, Monceau V, Ebrahimian T, Adam N, Wilkins RC, Sebastian S, Patel ZS, Huff JL, Simonetto C, Iwasaki T, Kaiser JC, Salomaa S, Moertl S, and Azimzadeh O
- Subjects
- Animals, Radiation, Ionizing, Referral and Consultation, Risk Assessment, Adverse Outcome Pathways, Cardiovascular Diseases etiology, Cardiovascular System
- Abstract
Background: The circulatory system distributes nutrients, signaling molecules, and immune cells to vital organs and soft tissues. Epidemiological, animal, and in vitro cellular mechanistic studies have highlighted that exposure to ionizing radiation (IR) can induce molecular changes in cellular and subcellular milieus leading to long-term health impacts, particularly on the circulatory system. Although the mechanisms for the pathologies are not fully elucidated, endothelial dysfunction is proven to be a critical event via radiation-induced oxidative stress mediators. To delineate connectivities of events specifically to cardiovascular disease (CVD) initiation and progression, the adverse outcome pathway (AOP) approach was used with consultation from field experts. AOPs are a means to organize information around a disease of interest to a regulatory question. An AOP begins with a molecular initiating event and ends in an adverse outcome via sequential linkages of key event relationships that are supported by evidence in the form of the modified Bradford-Hill criteria. Detailed guidelines on building AOPs are provided by the Organisation for Economic Cooperation and Development (OECD) AOP program. Here, we report on the questions and discussions needed to develop an AOP for CVD resulting from IR exposure. A recent workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations brought together experts from the OECD to present the AOP approach and tools with examples from the toxicology field. As part of this workshop, four working groups were formed to discuss the identification of adverse outcomes relevant to radiation exposures and development of potential AOPs, one of which was focused on IR-induced cardiovascular effects. Each working group comprised subject matter experts and radiation researchers interested in the specific disease area and included an AOP coach., Conclusion: The CVD working group identified the critical questions of interest for AOP development, including the exposure scenario that would inform the evidence, the mechanisms of toxicity, the initiating event, intermediate key events/relationships, and the type of data currently available. This commentary describes the four-day discussion of the CVD working group, its outcomes, and demonstrates how collaboration and expert consultation is vital to informing AOP construction.
- Published
- 2021
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31. PrP(c) deficiency and dasatinib protect mouse intestines against radiation injury by inhibiting of c-Src.
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Strup-Perrot C, Vozenin MC, Monceau V, Pouzoulet F, Petit B, Holler V, Perrot S, Desquibert L, Fouquet S, Souquere S, Pierron G, Rousset M, Thenet S, Cardot P, Benderitter M, Deutsch E, and Aigueperse J
- Subjects
- Animals, CSK Tyrosine-Protein Kinase, Caco-2 Cells, Humans, Mice, Mice, Inbred C57BL, Prion Proteins physiology, Whole-Body Irradiation, src-Family Kinases physiology, Dasatinib therapeutic use, Intestines radiation effects, Prion Proteins deficiency, Radiation Injuries prevention & control, src-Family Kinases antagonists & inhibitors
- Abstract
Background & Aim: Despite extensive study of the contribution of cell death and apoptosis to radiation-induced acute intestinal injury, our knowledge of the signaling mechanisms involved in epithelial barrier dysfunction remains inadequate. Because PrP(c) plays a key role in intestinal homeostasis by renewing epithelia, we sought to study its role in epithelial barrier function after irradiation., Design: Histology, morphometry and plasma FD-4 levels were used to examine ileal architecture, wound healing, and intestinal leakage in PrP(c)-deficient (KO) and wild-type (WT) mice after total-body irradiation. Impairment of the PrP(c) Src pathway after irradiation was explored by immunofluorescence and confocal microscopy, with Caco-2/Tc7 cells. Lastly, dasatinib treatment was used to switch off the Src pathway in vitro and in vivo., Results: The decrease in radiation-induced lethality, improved intestinal wound healing, and reduced intestinal leakage promoted by PrP(c) deficiency demonstrate its involvement in acute intestinal damage. Irradiation of Cacao2/Tc7 cells induced PrP(c) to target the nuclei associated with Src activation. Finally, the protective effect triggered by dasatinib confirmed Src involvement in radiation-induced acute intestinal toxicity., Conclusion: Our data are the first to show a role for the PrP(c)-Src pathway in acute intestinal response to radiation injury and offer a novel therapeutic opportunity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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32. Resident PW1+ Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension.
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Dierick F, Héry T, Hoareau-Coudert B, Mougenot N, Monceau V, Claude C, Crisan M, Besson V, Dorfmüller P, Marodon G, Fadel E, Humbert M, Yaniz-Galende E, Hulot JS, Marazzi G, Sassoon D, Soubrier F, and Nadaud S
- Subjects
- Animals, Cells, Cultured, Humans, Hypertension, Pulmonary pathology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Smooth, Vascular pathology, Rats, Stem Cells pathology, Hypertension, Pulmonary metabolism, Kruppel-Like Transcription Factors biosynthesis, Muscle, Smooth, Vascular metabolism, Stem Cells metabolism, Vascular Remodeling physiology
- Abstract
Rationale: Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1(+) progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro., Objective: To determine the role of pulmonary PW1(+) progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension., Methods and Results: We investigated their contribution during chronic hypoxia-induced vascular remodeling in Pw1(nLacZ+/-) mouse expressing β-galactosidase in PW1(+) cells and in differentiated cells derived from PW1(+) cells. PW1(+) progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1(+) cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1(+) cells and the proportion of β-gal(+) vascular SMC were increased, indicating a recruitment of PW1(+) cells and their differentiation into vascular SMC during early chronic hypoxia-induced neomuscularization. CXCR4 inhibition using AMD3100 prevented PW1(+) cells differentiation into SMC but did not inhibit their proliferation. Bone marrow transplantation experiments showed that the newly formed β-gal(+) SMC were not derived from circulating bone marrow-derived PW1(+) progenitor cells, confirming a resident origin of the recruited PW1(+) cells. The number of pulmonary PW1(+) cells was also increased in rats after monocrotaline injection. In lung from pulmonary arterial hypertension patients, PW1-expressing cells were observed in large numbers in remodeled vascular structures., Conclusions: These results demonstrate the existence of a novel population of resident SMC progenitor cells expressing PW1 and participating in pulmonary hypertension-associated vascular remodeling., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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33. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.
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Favaudon V, Caplier L, Monceau V, Pouzoulet F, Sayarath M, Fouillade C, Poupon MF, Brito I, Hupé P, Bourhis J, Hall J, Fontaine JJ, and Vozenin MC
- Subjects
- Animals, Apoptosis radiation effects, Blood Vessels radiation effects, Bronchi radiation effects, Dose-Response Relationship, Radiation, Female, Humans, Lung blood supply, Lung pathology, Mice, Mice, Inbred C57BL, Pulmonary Fibrosis pathology, Xenograft Model Antitumor Assays, Gamma Rays, Neoplasms pathology
- Abstract
In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue., (Copyright © 2014, American Association for the Advancement of Science.)
- Published
- 2014
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34. Epac contributes to cardiac hypertrophy and amyloidosis induced by radiotherapy but not fibrosis.
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Monceau V, Llach A, Azria D, Bridier A, Petit B, Mazevet M, Strup-Perrot C, To TH, Calmels L, Germaini MM, Gourgou S, Fenoglietto P, Bourgier C, Gomez AM, Escoubet B, Dörr W, Haagen J, Deutsch E, Morel E, and Vozenin MC
- Subjects
- Amyloidosis metabolism, Amyloidosis pathology, Animals, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms radiotherapy, Calcium metabolism, Cardiomegaly metabolism, Cardiomegaly pathology, Female, Fibrosis etiology, Fibrosis metabolism, Fibrosis pathology, Humans, Male, Mice, Mice, Inbred C57BL, Myocytes, Cardiac metabolism, Myocytes, Cardiac radiation effects, Radiation Injuries metabolism, Radiation Injuries pathology, Rats, Amyloidosis etiology, Cardiomegaly etiology, Guanine Nucleotide Exchange Factors metabolism, Heart radiation effects, Radiation Injuries etiology
- Abstract
Background: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target., Methods: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes., Results: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals., Conclusion: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
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35. Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFβ1 cascade involved in fibrogenesis.
- Author
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Monceau V, Meziani L, Strup-Perrot C, Morel E, Schmidt M, Haagen J, Escoubet B, Dörr W, and Vozenin MC
- Subjects
- Animals, Apolipoproteins E genetics, Blotting, Western, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Apolipoproteins E physiology, Dose-Response Relationship, Radiation, Fibrosis, Inflammation Mediators blood, Transforming Growth Factor beta1 metabolism
- Abstract
Aim: Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice., Methods and Results: ApoE-/- and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX). Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy) occurred in both strains of mice. Low dose irradiation (0.2 Gy) induced premature death in ApoE-/- mice (47% died at 20 weeks). Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-β1 and PAI-1) was measured earlier in cardiomyocytes isolated from ApoE-/- than in wt animals., Conclusion: The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages.
- Published
- 2013
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36. Therapeutic management of intestinal fibrosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa.
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Hamama S, Delanian S, Monceau V, and Vozenin MC
- Abstract
Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice.
- Published
- 2012
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37. [Pharmacological modulation of late radio-induced side effects].
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Bourgier C, Monceau V, Bourhis J, Deutsch E, and Vozenin MC
- Subjects
- Clinical Trials, Phase II as Topic, Dose-Response Relationship, Radiation, Epigenesis, Genetic, Extracellular Matrix drug effects, Extracellular Matrix radiation effects, Fibroblasts pathology, Fibroblasts radiation effects, Fibrosis, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Inflammation drug therapy, Inflammation etiology, Integrins physiology, Intercellular Signaling Peptides and Proteins physiology, Mesoderm radiation effects, Myoblasts pathology, Myoblasts radiation effects, Neoplasm Proteins physiology, Oxidative Stress, Protein Kinase Inhibitors therapeutic use, Radiation Injuries etiology, Radiation Tolerance genetics, Reactive Oxygen Species, Signal Transduction physiology, Anti-Inflammatory Agents therapeutic use, Antioxidants therapeutic use, Radiation Injuries drug therapy, Radiotherapy adverse effects
- Abstract
After normal tissue exposure to radiation therapy, late side effects can occur and may reduce patients' quality of life due to their progressive nature. Late toxicities occurrence is the main limiting factor of radiotherapy. Various biological disorders related to irradiation are involved in the development of late toxicities including fibrosis. The present review will focus on the recent physiopathological and molecular mechanisms described to be involved in the development of late radio-induced toxicities, that provide therapeutic perspective for pharmacomodulation., (Copyright © 2011 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)
- Published
- 2011
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38. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity.
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Monceau V, Pasinetti N, Schupp C, Pouzoulet F, Opolon P, and Vozenin MC
- Subjects
- Amides pharmacology, Animals, Bleomycin pharmacology, Connective Tissue Growth Factor genetics, Connective Tissue Growth Factor metabolism, Cytoskeleton metabolism, Cytoskeleton pathology, Endomyocardial Fibrosis metabolism, Female, Heart drug effects, Heart physiopathology, Heart radiation effects, Lung drug effects, Lung metabolism, Lung pathology, Lung radiation effects, Mice, Mice, Inbred C57BL, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Myocytes, Cardiac radiation effects, Pravastatin pharmacology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Pyridines pharmacology, Radiation Injuries metabolism, Radiation Pneumonitis metabolism, Radiation Pneumonitis prevention & control, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta genetics, Receptors, Transforming Growth Factor beta metabolism, Simvastatin pharmacology, Smad Proteins genetics, Smad Proteins metabolism, rho-Associated Kinases antagonists & inhibitors, rho-Associated Kinases genetics, rhoB GTP-Binding Protein genetics, rhoB GTP-Binding Protein metabolism, Endomyocardial Fibrosis prevention & control, Radiation Injuries prevention & control, Thorax radiation effects, rho-Associated Kinases metabolism
- Abstract
The medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibrogenic pathways (Smad and Rho/ROCK) in response to radiation-exposure to adult cardiomyocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibrogenic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibrogenic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (1) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (2) radioprotection, as applicable to the treatment of established radiation injury, for example in the case of radiation accidents or acts of terrorism.
- Published
- 2010
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39. Compartmentalized expression of three novel sarco/endoplasmic reticulum Ca2+ATPase 3 isoforms including the switch to ER stress, SERCA3f, in non-failing and failing human heart.
- Author
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Dally S, Monceau V, Corvazier E, Bredoux R, Raies A, Bobe R, del Monte F, and Enouf J
- Subjects
- Adult, Cell Line, DNA-Binding Proteins metabolism, Endoplasmic Reticulum Chaperone BiP, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Heart Failure genetics, Heat-Shock Proteins, Humans, Intracellular Space enzymology, Isoenzymes genetics, Isoenzymes metabolism, Middle Aged, Molecular Chaperones, Myocardium enzymology, Myocardium pathology, Myocytes, Cardiac enzymology, RNA, Messenger genetics, RNA, Messenger metabolism, Regulatory Factor X Transcription Factors, Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics, Transcription Factors metabolism, Transcription, Genetic, X-Box Binding Protein 1, Cell Compartmentation, Endoplasmic Reticulum enzymology, Endoplasmic Reticulum pathology, Heart Failure enzymology, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
- Abstract
The human sarco/endoplasmic reticulum (ER) Ca(2+)ATPase 3 (SERCA3) gene gives rise to SERCA3a-3f isoforms, the latter inducing ER stress in vitro. Here, we first demonstrated the co-expression of SERCA3a, -3d and -3f proteins in the heart. Evidence for endogenous proteins was obtained by using isoform-specific antibodies including a new SERCA3d-specific antibody, and either Western blotting of protein lysates or immunoprecipitation of membrane proteins. An immunolocalization study of both left ventricle tissue and isolated cardiomyocytes showed a distinct compartmentalization of the SERCA3 isoforms, as a uniform distribution of SERCA3a was detected while -3d and -3f isoforms were observed around the nucleus and in close vicinity of plasma membrane, respectively. Second, we studied their expressions in failing hearts including mixed (MCM) (n=1) and idiopathic dilated (IDCM) cardiomyopathies (n=4). Compared with controls (n=5), similar expressions of SERCA3a and -3d mRNAs were observed in all patients. In contrast, SERCA3f mRNA was found to be up-regulated in failing hearts (125+/-7%). Remarkably, overexpression of SERCA3f paralleled an increase in ER stress markers including processing of X-box-binding protein-1 (XBP-1) mRNA (176+/-24%), and expression of XBP-1 protein and glucose-regulated protein (GRP)78 (232+/-21%). These findings revisit the human heart's Ca(2+)ATPase system and indicate that SERCA3f may account for the mechanism of ER stress in vivo in heart failure.
- Published
- 2009
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40. Myocyte apoptosis during acute myocardial infarction in rats is related to early sarcolemmal translocation of annexin A5 in border zone.
- Author
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Monceau V, Belikova Y, Kratassiouk G, Robidel E, Russo-Marie F, and Charlemagne D
- Subjects
- Acute Disease, Animals, Annexin A5 genetics, Blotting, Western, Caspase 3, Caspases metabolism, Coronary Vessels physiology, DNA biosynthesis, DNA genetics, In Situ Nick-End Labeling, Ligation, Male, Rats, Rats, Wistar, Sodium-Potassium-Exchanging ATPase metabolism, Annexin A5 metabolism, Apoptosis physiology, Myocardial Infarction pathology, Myocytes, Cardiac physiology, Sarcolemma pathology
- Abstract
Annexin A5 is a Ca2+-dependent phospholipid binding protein well known for its high phosphatidylserine affinity. In vitro, translocation to sarcolemma and externalization of endogenous annexin A5 in the cardiomyocyte has recently been demonstrated to exert a proapoptotic effect. To determine whether these in vitro findings occurred in vivo, we performed myocardial infarction (MI) and studied the time course of apoptosis and annexin A5 localization (0.5 to 8 h) in the border zone around the infarcted area. This zone that was defined as Evans blue unstained and triphenyltetrazolium chloride (TTC) stained, represented 42.3 +/- 5.5% of the area at risk and showed apoptotic characteristics (significant increases in caspase 3 activity 2.3-fold at 0.5 h; P < 0.05), transferase-mediated dUTP nick-end labeling-positive cardiomyocytes (15.8 +/- 0.8% at 8 h), and DNA ladder. When compared with sham-operated rats, we found that in this area, annexin A5 was translocated to the sarcolemma as early as 0.5 h after MI and that translocation increased with time. Moreover, the amount of annexin A5 was unchanged in the border zone and decreased in the infarcted area after 1 h (77.1 +/- 4.8%; P < 0.01 vs. perfused area), suggesting a release in the latter but not in the former. In conclusion, we demonstrated that annexin A5 translocation is an early and rapid event of the whole border zone, likely due to Ca2+ increase. Part of this translocation occurred in areas where apoptosis was later detected and suggests that in vivo as in vitro annexin A5 might be involved in the regulation of early apoptotic events during cardiac pathological situations.
- Published
- 2006
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41. Ca2+-ATPases in non-failing and failing heart: evidence for a novel cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2 isoform (SERCA2c).
- Author
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Dally S, Bredoux R, Corvazier E, Andersen JP, Clausen JD, Dode L, Fanchaouy M, Gelebart P, Monceau V, Del Monte F, Gwathmey JK, Hajjar R, Chaabane C, Bobe R, Raies A, and Enouf J
- Subjects
- Adult, Calcium Signaling, Calcium-Transporting ATPases genetics, Cation Transport Proteins, Cell Line, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Humans, Membrane Proteins metabolism, Middle Aged, Myocardium pathology, Plasma Membrane Calcium-Transporting ATPases, Protein Isoforms, RNA, Messenger genetics, RNA, Messenger metabolism, Recombinant Proteins metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Calcium-Transporting ATPases metabolism, Cardiomyopathies enzymology, Cardiomyopathies pathology, Endoplasmic Reticulum enzymology, Myocardium cytology, Myocardium enzymology, Sarcoplasmic Reticulum enzymology
- Abstract
We recently documented the expression of a novel human mRNA variant encoding a yet uncharacterized SERCA [SR (sarcoplasmic reticulum)/ER (endoplasmic reticulum) Ca2+-ATPase] protein, SERCA2c [Gélébart, Martin, Enouf and Papp (2003) Biochem. Biophys. Res. Commun. 303, 676-684]. In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. In microsomes prepared from transfected cells, SERCA2c showed a lower apparent affinity for cytosolic Ca2+ than SERCA2a and a catalytic turnover rate similar to SERCA2b. We further demonstrated the expression of the endogenous SERCA2c protein in protein lysates isolated from heart left ventricles using a newly generated SERCA2c-specific antibody. Relative to the known uniform distribution of SERCA2a and SERCA2b in cardiomyocytes of the left ventricle tissue, SERCA2c was only detected in a confined area of cardiomyocytes, in close proximity to the sarcolemma. This finding led us to explore the expression of the presently known cardiac Ca2+-ATPase isoforms in heart failure. Comparative expression of SERCAs and PMCAs (plasma-membrane Ca2+-ATPases) was performed in four nonfailing hearts and five failing hearts displaying mixed cardiomyopathy and idiopathic dilated cardiomyopathies. Relative to normal subjects, cardiomyopathic patients express more PMCAs than SERCA2 proteins. Interestingly, SERCA2c expression was significantly increased (166+/-26%) in one patient. Taken together, these results demonstrate the expression of the novel SERCA2c isoform in the heart and may point to a still unrecognized role of PMCAs in cardiomyopathies.
- Published
- 2006
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42. Association of annexin A5 with Na+/Ca2+ exchanger and caveolin-3 in non-failing and failing human heart.
- Author
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Camors E, Charue D, Trouvé P, Monceau V, Loyer X, Russo-Marie F, and Charlemagne D
- Subjects
- Blotting, Western, Humans, Immunoprecipitation, Multiprotein Complexes, Quaternary Ammonium Compounds chemistry, Reference Values, Surface Plasmon Resonance, Annexin A5 metabolism, Caveolin 3 metabolism, Heart Failure metabolism, Myocardium metabolism, Sodium-Calcium Exchanger metabolism
- Abstract
Annexin A5 is a Ca2+ dependent phosphatidylserine binding protein mainly located in the T-tubules and sarcolemma of cardiomyocytes. Our objectives were to determine whether annexin A5 was associated with various protein(s) and whether such an association was modified in failing (F) hearts. The association between annexin A5 and the cardiac Na+/Ca2+ exchanger (NCX) was demonstrated by immunohistofluorescence, annexin A5-biotin overlay and co-immunoprecipitations (IPs) performed with microsomal preparations (MPs) from non-failing (NF) (n = 8) and F (dilated cardiomyopathy, n = 7) human hearts. We moreover found caveolin-3 in the immunoprecipitates, indicating the presence of multimolecular subsarcolemmal complexes. Surface plasmon resonance assays in NF MPs allowed us to demonstrate direct interaction between the NCX and caveolin-3 and immobilized annexin A5. Interaction was Ca2+-dependent and inhibited by the specific antibody. In addition, dissociation by zwittergent 3-14 (ZW 3-14) of the complexes from MPs increased specific interactions. In F hearts, specific interactions were blunted in native MPs but were fully recovered after treatment with ZW 3-14. In conclusion, we demonstrated that a direct interaction between annexin A5 and the cardiac NCX occurs in complexes including caveolin-3. In F hearts, despite the increase in the exchanger level, almost all of the NCX was involved in complexes. These interactions probably occurred in the intracytoplasmic regulatory loop of the exchanger, suggesting a different regulation of the exchanger in heart failure, consistent with a role in altered Ca2+ handling.
- Published
- 2006
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43. Role of myocardial neuronal nitric oxide synthase-derived nitric oxide in beta-adrenergic hyporesponsiveness after myocardial infarction-induced heart failure in rat.
- Author
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Bendall JK, Damy T, Ratajczak P, Loyer X, Monceau V, Marty I, Milliez P, Robidel E, Marotte F, Samuel JL, and Heymes C
- Subjects
- Adrenergic beta-Agonists pharmacology, Animals, Autocrine Communication, Caveolin 3, Caveolins metabolism, Dobutamine pharmacology, Enzyme Induction, Heart Failure drug therapy, Heart Failure etiology, Isoproterenol pharmacology, Male, Myocardial Contraction drug effects, Nitric Oxide Synthase Type I, Rats, Rats, Wistar, Ryanodine Receptor Calcium Release Channel metabolism, Sarcolemma metabolism, Ventricular Dysfunction, Left enzymology, Ventricular Dysfunction, Left etiology, Heart Failure enzymology, Myocardial Contraction physiology, Myocardial Infarction complications, Myocardium enzymology, Nerve Tissue Proteins physiology, Nitric Oxide physiology, Nitric Oxide Synthase physiology, Receptors, Adrenergic, beta physiology
- Abstract
Background: An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined., Methods and Results: Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats (P<0.05 and P<0.001 versus shams, respectively). This was associated with translocation of NOS1 from the ryanodine receptor to the sarcolemma through interactions with caveolin-3 in HF hearts. With ex vivo and in vivo pressure-volume analysis, cardiac NOS1-derived NO was found to be negatively inotropic in shams but not HF hearts. Ventricular elastance (E(es)) was significantly reduced in HF rats (P<0.05), and tau, the time constant of left ventricular relaxation, was prolonged (both P<0.05). Acute NOS1 inhibition significantly increased E(es) by 33+/-3% and tau by 17+/-2% (P<0.05) in shams, although these effects were significantly attenuated in HF hearts. beta-Adrenergic stimulation induced a marked increase in systolic performance in sham hearts, with the responses being significantly blunted in HF hearts. E(es) increased by 163+/-42% (P<0.01) in sham hearts and 56+/-9% in HF hearts, and LV +dP/dt increased by 97+/-9% (P<0.01) in shams and 37+/-7% (P<0.05) in the HF group. Interestingly, preferential NOS1 inhibition enhanced the blunted responses of LV +dP/dt and E(es) to beta-adrenergic stimulation in HF rats but had no effect in shams., Conclusions: These results provide the first evidence that increased NOS1-derived NO production may play a role in the autocrine regulation of myocardial contractility in HF.
- Published
- 2004
- Full Text
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