title: Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene.
abstract: Congestive heart failure is the common endpoint of various cardiac diseases representing a leading cause of cardiovascular mortality in Western countries. Characteristic functional alterations of the failing heart are explained by expressional changes of myocardial regulatory proteins; however, little is known about underlying mechanisms regulating cardiac gene expression in the failing heart. Here, we address the specific role of transcription factor CREM for cardiac function in CREM mutant mice with complete inactivation of the CREM gene. We show that CREM mutant mice display distinct alterations of cardiac function resembling characteristic functional defects of the failing heart. Left ventricular hemodynamic assessment of CREM mutant mice revealed impairment of both cardiac contraction and relaxation in basal state, as well as a decreased responsiveness to beta-adrenergic stimulation. The diminished cardiac contractile performance was associated with a selective down-regulation of beta1-adrenergic receptors and a decreased ventricular expression of SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. The cardiac phenotype of CREM mutant mice provides the first evidence that CREM represents an important key regulator of cardiac gene expression, which is essential for normal left ventricular contractile performance and response to beta-adrenoreceptor stimulation.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Germany. mullerf@uni-muenster.de
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.forename: Geertje
authors.initials: G
authors.lastname: Lewin
authors.forename: Marek
authors.initials: M
authors.lastname: Matus
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.forename: Joachim
authors.initials: J
authors.lastname: Wistuba
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schmitz
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004280:Dobutamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009200:Myocardial Contraction; D012097:Repressor Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D016019:Survival Analysis; D018487:Ventricular Dysfunction, Left / Q000209:etiology
chemical_list: D000318:Adrenergic beta-Agonists; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D004280:Dobutamine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases