Expression of the β-myosin heavy chain (β-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of β-adrenergic tone upregulates β-MHC expression. However, it is unknown whether the duration of the β-adrenergic inhibition and β-MHC expression are related. Here, we evaluated the effects of intermittent β-blockade on cardiac β-MHC expression. To this end, the β-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac β-adrenergic responsiveness. Under these conditions, β-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking β1- but not β2-adrenergic receptors (β-AR) indicating that β-MHC expression is regulated in a β1-AR-dependent manner. In β1-AR knockout mice, the baseline β-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent β-blockade on β-MHC expression in mice with systolic dysfunction, in which an increased β-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of β-MHC expression. Intermittent β-blockade decreased β-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect β-MHC expression on its own but antagonizes catecholamine effects on β-MHC expression. In conclusion, a direct relationship occurs between the duration of the β-adrenergic inhibition and β-MHC expression through the β1-AR.

Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart / Maccari, S.; Pace, V.; Barbagallo, F.; Stati, T.; Ambrosio, C.; Gro, M. C.; Molinari, P.; Vezzi, V.; Catalano, L.; Matarrese, P.; Patrizio, M.; Rizzi, R.; Marano, G.. - In: EUROPEAN JOURNAL OF PHARMACOLOGY. - ISSN 0014-2999. - 882:(2020). [10.1016/j.ejphar.2020.173287]

Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart

Pace V.;Barbagallo F.;Rizzi R.;
2020

Abstract

Expression of the β-myosin heavy chain (β-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of β-adrenergic tone upregulates β-MHC expression. However, it is unknown whether the duration of the β-adrenergic inhibition and β-MHC expression are related. Here, we evaluated the effects of intermittent β-blockade on cardiac β-MHC expression. To this end, the β-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac β-adrenergic responsiveness. Under these conditions, β-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking β1- but not β2-adrenergic receptors (β-AR) indicating that β-MHC expression is regulated in a β1-AR-dependent manner. In β1-AR knockout mice, the baseline β-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent β-blockade on β-MHC expression in mice with systolic dysfunction, in which an increased β-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of β-MHC expression. Intermittent β-blockade decreased β-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect β-MHC expression on its own but antagonizes catecholamine effects on β-MHC expression. In conclusion, a direct relationship occurs between the duration of the β-adrenergic inhibition and β-MHC expression through the β1-AR.
2020
gene expression; β-adrenergic receptors; β-blockers; β-myosin heavy chain
01 Pubblicazione su rivista::01a Articolo in rivista
Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart / Maccari, S.; Pace, V.; Barbagallo, F.; Stati, T.; Ambrosio, C.; Gro, M. C.; Molinari, P.; Vezzi, V.; Catalano, L.; Matarrese, P.; Patrizio, M.; Rizzi, R.; Marano, G.. - In: EUROPEAN JOURNAL OF PHARMACOLOGY. - ISSN 0014-2999. - 882:(2020). [10.1016/j.ejphar.2020.173287]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1566128
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