Mineralocorticoid receptor overexpression in embryonic stem cell-derived cardiomyocytes increases their beating frequency

Autor: Le Menuet, Damien, Munier, Mathilde, Meduri, Géri, Viengchareun, Say, Lombès, Marc
Přispěvatelé: Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'Endocrinologie et Maladies de la reproduction, This work was supported by the European Section of Aldosterone Council (ESAC) (to ML and DL), the Programme National de Recherche Reproduction Endocrinologie (PNRRE), the Institut National de la Santé et de la Recherche Médicale (Inserm) and the Université Paris-Sud 11., Lombes, Marc
Jazyk: angličtina
Rok vydání: 2010
Předmět:
MESH: Cell Differentiation
MESH: Mice
Transgenic
MESH: Myocardial Contraction
MESH: Myocytes
Cardiac
MESH: Cyclic Nucleotide-Gated Cation Channels
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
MESH: Aldosterone Antagonists
MESH: Receptors
Mineralocorticoid
[SDV.BDD] Life Sciences [q-bio]/Development Biology
MESH: Up-Regulation
MESH: Membrane Potentials
MESH: Animals
MESH: Heart Rate
MESH: Embryonic Stem Cells
MESH: Mice
[SDV.BDD]Life Sciences [q-bio]/Development Biology
MESH: RNA
Messenger
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
MESH: Calcium Channels
L-Type
MESH: Humans
MESH: Time Factors
MESH: Potassium Channels
Inwardly Rectifying
MESH: Potassium Channels
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
MESH: Cell Line
[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
MESH: Spironolactone
Zdroj: Cardiovascular Research
Cardiovascular Research, Oxford University Press (OUP), 2010, 87 (3), pp.467-75. ⟨10.1093/cvr/cvq087⟩
ISSN: 0008-6363
DOI: 10.1093/cvr/cvq087⟩
Popis: International audience; AIMS: Cardiac mineralocorticoid receptor (MR) activation triggers adverse cardiovascular events that could be efficiently prevented by mineralocorticoid antagonists. To gain insights into the pathophysiological role of MR function, we established embryonic stem (ES) cell lines from blastocysts of transgenic mice overexpressing the human MR driven by its proximal P1 or distal P2 promoter and presenting with cardiomyopathy, tachycardia, and arrhythmia. Cardiomyocyte differentiation allowed us to investigate the molecular mechanisms contributing to MR-mediated cardiac dysfunction. METHODS AND RESULTS: During cardiac differentiation, wild-type (WT) and recombinant ES cell cultures and excised beating patches expressed endogenous MR along with cardiac gene markers. The two-fold increase in MR protein detected in P1.hMR and P2.hMR cardiomyocytes led to a parallel increase in the spontaneous beating frequency of hMR-overexpressing cardiomyocytes compared with WT. The MR-mediated chronotropic effect was ligand-independent, could be partially repressed by spironolactone, and was accompanied by a significant two- to four-fold increase in mRNA and protein levels of the pacemaker channel HCN1, generating depolarizing If currents, thus revealing a potential new MR target. This was associated with modification in the expression of HCN4, the inward-rectifier potassium channel Kir2.1, and the L-type voltage-dependent calcium channel Cav1.2. CONCLUSION: We demonstrate that the amplification of MR signalling in ES-derived cardiomyocytes has a major impact on cardiomyocyte contractile properties through an important remodelling of ion channel expression, contributing to arrhythmias. Our results highlight the prominent role of MR function in cardiac physiology and support the benefit of MR antagonists in the management of cardiac dysfunctions.
Databáze: OpenAIRE
Externí odkaz: