title: Conditional glucocorticoid receptor expression in the heart induces atrio-ventricular block.
abstract: Corticosteroid hormones (aldosterone and glucocorticoids) and their receptors are now recognized as major modulators of cardiovascular pathophysiology, but their specific roles remain elusive. Glucocorticoid hormones (GCs), which are widely used to treat acute and chronic diseases, often have adverse cardiovascular effects such as heart failure, hypertension, atherosclerosis, or metabolic alterations. The direct effects of GC on the heart are difficult to evaluate, as changes in plasma GC concentrations have multiple consequences due to the ubiquitous expression of the glucocorticoid receptor (GR), resulting in secondary effects on cardiac function. We evaluated the effects of GR on the heart in a conditional mouse model in which the GR was overexpressed solely in cardiomyocytes. The transgenic mice displayed electrocardiogram (ECG) abnormalities: a long PQ interval, increased QRS and QTc duration as well as chronic atrio-ventricular block, without cardiac hypertrophy or fibrosis. The ECG alterations were reversible on GR expression shutoff. Isolated ventricular cardiomyocytes showed major ion channel remodeling, with decreases in I(Na), I(to), and I(Kslow) activity and changes in cell calcium homeostasis (increase in C(al), in Ca2+ transients and in sarcoplasmic reticulum Ca2+ load). This phenotype differs from that observed in mice overexpressing the mineralocorticoid receptor in the heart, which displayed ventricular arrhythmia. Our mouse model highlights novel effects of GR activation in the heart indicating that GR has direct and specific cardiac effects in the mouse.
authors.affiliation: INSERM U772, Paris, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Sainte-Marie
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.forename: Romain
authors.initials: R
authors.lastname: Perrier
authors.forename: Laurence
authors.initials: L
authors.lastname: Mangin
authors.forename: Christelle
authors.initials: C
authors.lastname: Soukaseum
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benitah
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001283:Atrioventricular Node / Q000503:physiopathology*; D002110:Caffeine / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D004562:Electrocardiography; D005938:Glucocorticoids / Q000378:metabolism*; D006327:Heart Block / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D002110:Caffeine; D002118:Calcium