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Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice
S Engelhardt1, L Hein, F Wiesmann
1Institut für Pharmakologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Abstract:
Stimulation of cardiac beta1-adrenergic receptors is the main mechanism that increases heart rate and contractility. Consequently, several pharmacological and gene transfer strategies for the prevention of heart failure aim at improving the function of the cardiac beta-adrenergic receptor system, whereas current clinical treatment favors a reduction of cardiac stimulation. To address this controversy, we have generated mice with heart-specific overexpression of beta1-adrenergic receptors. Their cardiac function was investigated in organ bath experiments as well as in vivo by cardiac catheterization and by time-resolved NMR imaging. The transgenic mice had increased cardiac contractility at a young age but also developed marked myocyte hypertrophy (3.5-fold increase in myocyte area). This increase was followed by progressive heart failure with functional and histological deficits typical for humans with heart failure. Contractility was reduced by approximately 50% in 35-week-old mice, and ejection fraction was reduced down to a minimum of approximately 20%. We conclude that overexpression of beta1-adrenergic receptors in the heart may lead to a short-lived improvement of cardiac function, but that increased beta1-adrenergic receptor signalling is ultimately detrimental.
Insights
Overexpressing beta1-adrenergic receptors in the heart boosts function initially but leads to heart failure. This highlights the detrimental effects of excessive beta1-adrenergic receptor signaling in cardiac health.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Cardiac beta1-adrenergic receptors regulate heart rate and contractility.
- Therapeutic strategies for heart failure are divided on modulating cardiac stimulation.
- Understanding beta1-adrenergic receptor system function is crucial for heart failure treatment.
Purpose of the Study:
- To investigate the long-term effects of heart-specific beta1-adrenergic receptor overexpression.
- To resolve the controversy regarding cardiac stimulation in heart failure treatment.
- To determine the impact of increased beta1-adrenergic receptor signaling on cardiac function.
Main Methods:
- Generation of mice with heart-specific beta1-adrenergic receptor overexpression.
- Assessment of cardiac function using organ bath experiments.
- In vivo analysis via cardiac catheterization and time-resolved NMR imaging.
Main Results:
- Transgenic mice exhibited increased cardiac contractility and myocyte hypertrophy.
- Progressive heart failure developed, with functional and histological deficits.
- Significant reductions in contractility and ejection fraction were observed in older mice.
Conclusions:
- Overexpression of beta1-adrenergic receptors provides transient cardiac function improvement.
- Sustained elevation of beta1-adrenergic receptor signaling is ultimately detrimental to cardiac health.
- This study underscores the complex role of beta1-adrenergic receptors in heart function and failure.