TY - JOUR
T1 - Propranolol promotes Egr1 gene expression in cardiomyocytes via β-adrenoceptors
AU - Patrizio, Mario
AU - Musumeci, Marco
AU - Stati, Tonino
AU - Fecchi, Katia
AU - Mattei, Elisabetta
AU - Catalano, Liviana
AU - Marano, Giuseppe
PY - 2008/6/10
Y1 - 2008/6/10
N2 - Recent research has revealed that propranolol, a β-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 β-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 ≈ 19-fold increase of Egr1 mRNA expression in left ventricular myocardium along with a ≈ 2.1-fold increase of Egr1 protein expression. Isoproterenol, a nonselective β-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 β
1- and β
2-adrenoceptors indicating that propranolol increases Egr1 mRNA expression in a β-adrenoceptor-dependent manner. The role of β-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 β-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.
AB - Recent research has revealed that propranolol, a β-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 β-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 ≈ 19-fold increase of Egr1 mRNA expression in left ventricular myocardium along with a ≈ 2.1-fold increase of Egr1 protein expression. Isoproterenol, a nonselective β-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 β
1- and β
2-adrenoceptors indicating that propranolol increases Egr1 mRNA expression in a β-adrenoceptor-dependent manner. The role of β-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 β-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.
KW - Adrenoceptors
KW - Cardiomyocytes
KW - Egr1
KW - Gene expression
KW - Propranolol
UR - http://www.scopus.com/inward/record.url?scp=44149103097&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44149103097&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2008.04.017
DO - 10.1016/j.ejphar.2008.04.017
M3 - Article
C2 - 18485346
AN - SCOPUS:44149103097
VL - 587
SP - 85
EP - 89
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -