title: Propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors.
abstract: Recent research has revealed that propranolol, a beta-adrenoceptor antagonist, causes extracellular signal-regulated kinase (ERK) cascade activation, nuclear translocation of phospho-ERK and increased transcriptional activity in cultured cell lines. Given the importance of beta-adrenoceptor antagonists in the treatment of heart failure, we evaluated the capability of propranolol of promoting the ERK-dependent gene expression at the cardiomyocyte level. To this end, the gene expression of the early growth response factor 1 (Egr1), a well-recognized indicator of nuclear extracellular signal-regulated kinase 1/2 (ERK1/2) activation, was assessed by quantitative real-time RT-PCR in vivo as well as in vitro experiments. Propranolol, administered at the dose of 10 mg/kg/day in C57BL/6 mice, caused a approximately 19-fold increase of Egr1 mRNA expression in left ventricular myocardium along with a approximately 2.1-fold increase of Egr1 protein expression. Isoproterenol, a nonselective beta-adrenoceptor agonist, also increased Egr1 mRNA and protein expression but to a lesser degree. Remarkably, isoproterenol administration was associated with the development of cardiac hypertrophy, whereas propranolol-treated mice showed a completely normal cardiac morphology. The effect of propranolol on Egr1 mRNA expression was abrogated in mice lacking beta(1)- and beta(2)-adrenoceptors indicating that propranolol increases Egr1 mRNA expression in a beta-adrenoceptor-dependent manner. The role of beta-adrenoceptors was further confirmed by showing that propranolol was able to increase Egr1 mRNA and protein levels in cultured neonatal cardiomyocytes. Collectively, these results indicate that propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors with a mechanism which is independent of its ability to antagonize the effects of catecholamines. It is also suggested that cardiomyocyte growth and Egr1 gene overexpression are not obligate processes.
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Patrizio
authors.forename: Marco
authors.initials: M
authors.lastname: Musumeci
authors.forename: Tonino
authors.initials: T
authors.lastname: Stati
authors.forename: Katia
authors.initials: K
authors.lastname: Fecchi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattei
authors.forename: Liviana
authors.initials: L
authors.lastname: Catalano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marano
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002395:Catecholamines / Q000378:metabolism; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D004562:Electrocardiography; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D011433:Propranolol