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Published on: October 3, 2019
Propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors
Mario Patrizio1, Marco Musumeci, Tonino Stati
1Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy.
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.
Insights
Propranolol, a beta-blocker, activates ERK signaling and increases Egr1 gene expression in heart cells via beta-adrenoceptors. This effect is independent of catecholamine antagonism and does not cause cardiac hypertrophy.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Beta-adrenoceptor antagonists like propranolol are crucial in heart failure treatment.
- Propranolol has been shown to activate the extracellular signal-regulated kinase (ERK) cascade in cell lines.
Purpose of the Study:
- To investigate propranolol's ability to promote ERK-dependent gene expression in cardiomyocytes.
- To assess the role of beta-adrenoceptors in propranolol-induced gene expression.
Main Methods:
- Quantitative real-time RT-PCR and Western blotting were used to measure Egr1 (Early Growth Response 1) expression in vivo (mice) and in vitro (neonatal cardiomyocytes).
- Experiments involved propranolol and isoproterenol administration in wild-type and beta-adrenoceptor knockout mice.
Main Results:
- Propranolol significantly increased Egr1 mRNA and protein expression in mouse hearts and cultured cardiomyocytes.
- Isoproterenol also increased Egr1 but induced cardiac hypertrophy, unlike propranolol.
- Propranolol's effect on Egr1 expression was dependent on beta(1)- and beta(2)-adrenoceptors and independent of catecholamine antagonism.
Conclusions:
- Propranolol promotes Egr1 gene expression in cardiomyocytes through a beta-adrenoceptor-dependent mechanism.
- This effect is separate from its beta-blockade activity and does not lead to cardiac hypertrophy.
- Cardiomyocyte growth and Egr1 overexpression are not necessarily linked.
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