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dc.contributor.author Abi-Gerges, Aniella
dc.contributor.author Sassi, Yassine
dc.contributor.author Mougenot, Nathalie
dc.contributor.author Jacquet, Adeline
dc.contributor.author Engelhardt, Stefan
dc.contributor.author Hatem, Stephanie N.
dc.contributor.author Hulot, Jean-Sebastien
dc.contributor.author Lompre, Anne-Marie
dc.date.accessioned 2017-10-19T12:51:57Z
dc.date.available 2017-10-19T12:51:57Z
dc.date.copyright 2011 en_US
dc.date.issued 2017-10-19
dc.identifier.issn 1524-4571 en_US
dc.identifier.uri http://hdl.handle.net/10725/6363
dc.description.abstract Rationale: Transporters of the ABCC family, called MRP4 and MRP5, have been described to control cAMP homeostasis by extruding it from various cell types. Objective: The aim of our study was to determine the role of MRP4 in cAMP homeostasis and heart function and its impact on cardiac hypertrophy (CH). Methods and results: MRP4 KO mice and MRP4 KO with cardiac overexpression of the HCN-based cAMP sensor were used. Echocardiography and morphology studies showed that 3 month-old MRP4 KO mice displayed normal cardiac function (FS: 35.7% ± 1.02 in KO vs 36% ± 1.97 in WT) and cardiac phenotype (HW/TL: 7.59 ± 0.14 in WT mice vs 7.75 ± 0.15 in KO) in basal condition. Stimulation of WT and MRP4 KO mice by increasing concentrations of isoproterenol (ISO: 0.1μg/kg to 3 mg/kg) induced dose-dependent positive inotropic and chronotropic effects but there was no difference in the rate of contraction (Vmax: 11214 ± 682 in WT vs 10697 ± 691 in KO) or in the heart rate (724 ± 21 in WT vs 711 ± 21 in KO) between both groups. Cardiac myocytes were isolated from WT and MRP4 KO mice with cardiac expression of the HCN-based FRET sensor and intracellular cAMP concentrations were measured by FRET. Application of ISO (1nM) induced a similar increase in cAMP level in WT and MRP4 KO mice (YFP/CFP: 4.4 ± 0.15 in WT vs 4.1 ± 0.44 in KO cells), whereas cAMP signal was greater in MRP4 KO compared to WT mice after PDE inhibition by IBMX (ISO 1nM + IBMX 300µM: 8.1 ± 0.6 in WT vs 11.8 ± 0.62 in KO cells; p<0.01). PDE3A and PDE4A mRNA level was 1.6 fold higher in the myocardium of MRP4 KO compared to WT mice. MRP4 KO mice displayed age-dependent CH (HW/TL in 9 month-old mice: 9.8 ± 0.57 in KO vs 7.82 ± 0.13 in WT mice; p<0.01). 3 month-old MRP4 KO and WT mice were subjected to thoracic aortic clamping (TAC) or sham operated (Sh) and CH was assessed at 12 weeks after the surgery by echocardiography and morphometric studies. Heart function was also examined by hemodynamic technique in basal conditions and upon a β-adrenergic stimulation in WT (Sh and TAC) and MRP4 KO (Sh and TAC) mice. Alteration of left ventricular dP/dt upon β-adrenergic stimulation after TAC was more severe in MRP4 KO compared to WT mice. Conclusion: Taken together, our results show that both PDEs and MRP4 are important in cAMP homeostasis. en_US
dc.language.iso en en_US
dc.title MRP4 en_US
dc.type Article en_US
dc.description.version Published en_US
dc.title.subtitle a novel protein involved in camp homeostasis in the heart en_US
dc.author.school SOM en_US
dc.author.idnumber 201402416 en_US
dc.author.department N/A en_US
dc.description.embargo N/A en_US
dc.relation.journal Circulation Research en_US
dc.journal.volume 109, Suppl.1 en_US
dc.article.pages AP211 en_US
dc.keywords Cardiac hypertrophy en_US
dc.keywords Beta-adrenergic receptor agonists en_US
dc.keywords Imaging agents en_US
dc.identifier.ctation Abi-Gerges, A., Sassi, Y., Mougenot, N., Jacquet, A., Engelhardt, S., Hatem, S. N., ... & Lompré, A. M. (2011). Abstract P211: MRP4: A Novel Protein Involved in Camp Homeostasis in the Heart. Circulation Research, 9, Suppl 1. en_US
dc.author.email aniella.abigerges@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://www.ahajournals.org/doi/abs/10.1161/res.109.suppl_1.AP211 en_US
dc.note POSTER SESSION 3 Session title: Hypertrophic signaling pathways en_US
dc.orcid.id https://orcid.org/0000-0001-9974-4023 en_US
dc.author.affiliation Lebanese American University en_US

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