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Intermittent β-adrenergic blockade downregulates the gene expression of β-myosin heavy chain in the mouse heart
Sonia Maccari1, Valentina Pace2, Federica Barbagallo3
1Center for Gender-Specific Medicine, National Institute of Health, Rome, Italy.
Insights
Intermittent beta-blockade reduces cardiac beta-myosin heavy chain (β-MHC) expression, particularly through the β1-adrenergic receptor (β1-AR). This finding reveals a direct link between beta-adrenergic inhibition duration and β-MHC regulation in the heart.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Cardiac β-myosin heavy chain (β-MHC) expression is critical for heart function and tightly regulated.
- Increased β-MHC expression can be detrimental, especially under cardiac stress.
- Continuous β-adrenergic inhibition typically upregulates β-MHC, but the role of inhibition duration was unclear.
Purpose of the Study:
- To investigate the effect of intermittent β-blockade on cardiac β-MHC expression.
- To determine if β1- or β2-adrenergic receptors mediate the regulation of β-MHC expression.
- To assess the impact of intermittent β-blockade on β-MHC expression in a model of systolic dysfunction.
Main Methods:
- Administered propranolol daily to mice for 14 days, creating intermittent drug-free periods.
- Measured β-MHC expression in wild-type, β1-adrenergic receptor knockout, and β2-adrenergic receptor knockout mice.
- Evaluated the effects in mice with post-myocardial infarction systolic dysfunction.
- Conducted in vitro studies to elucidate the mechanism of propranolol action.
Main Results:
- Intermittent propranolol administration significantly decreased β-MHC expression by approximately 75%.
- This reduction was dependent on β1-adrenergic receptors, as it was abolished in β1-AR knockout mice.
- Baseline β-MHC expression was fourfold higher in β1-AR knockout mice.
- In mice with systolic dysfunction, intermittent β-blockade reduced β-MHC expression and attenuated cardiac dysfunction.
- In vitro, propranolol antagonized catecholamine effects on β-MHC expression without affecting it directly.
Conclusions:
- A direct relationship exists between the duration of β-adrenergic inhibition and cardiac β-MHC expression.
- Regulation of β-MHC expression by intermittent β-blockade is primarily mediated through the β1-adrenergic receptor.
- Intermittent β-blockade may be a therapeutic strategy to manage cardiac dysfunction associated with altered β-MHC expression.
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.
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