Abstract
Chronic stimulation of cardiac beta1-adrenergic receptors contributes
to disease progression and mortality in patients and animal models
of heart failure. To search for the mechanism of adrenergic impairment
of cardiac function in vivo, we studied transgenic mice with cardiac-specific
overexpression of beta1-adrenergic receptors. Transgenic mice with
cardiac overexpression of beta1-adrenergic receptors showed progressive
left ventricular fibrosis starting at 4 months of age. Left ventricular
catheterization revealed a modest enhancement of contractility and
relaxation at 2 months of age, followed by progressive dysfunction
in both parameters and ultimately cardiac failure. When the effects
of endogenous catecholamines were blocked by the b-receptor antagonist
propranolol, maximal rate of contractility (dp/dtmax) and maximal
rate of relaxation (dp/dtmin) were significantly blunted in 2-month-old
beta1-receptor transgenic mice. Isolated cardiomyocytes from these
animals displayed markedly altered calcium transients with significant
prolongation of the intracellular calcium transient compared with
nontransgenic littermates. We determined the expression of sarcoplasmic
reticulum proteins involved in calcium handling by RNase protection
assay and by immunoblotting. Although the expression of calsequestrin,
triadin, and phospholamban was not altered, we observed a progressive
decrease in junctin abundance in beta1-receptor transgenic mice (Pbeta1-adrenergic
receptors.
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