Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice.
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.
Engelhardt
S
S
Institut für Pharmakologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Hein
L
L
Wiesmann
F
F
Lohse
M J
MJ
D000375:Aging; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology; D015870:Gene Expression; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D009924:Organ Culture Techniques; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*
D018342:Receptors, Adrenergic, beta-1