Early impairment of calcium handling and altered expression of junctin in hearts of mice overexpressing the beta(1)-adrenergic receptor

Chronic stimulation of cardiac beta (1)-adrenergic receptors contributes to disease progression and mortality in patients and animal models of heart f ailure. To search for the mechanism of adrenergic impairment of cardiac fun ction in vivo, we studied transgenic mice with cardiac-specific overexpress ion of beta (1)-adrenergic receptors. Transgenic mice with cardiac overexpr ession of beta (1)-adrenergic receptors showed progressive left ventricular fibrosis starting at 4 months of age. Left ventricular catheterization rev ealed a modest enhancement of contractility and relaxation at 2 months of a ge, followed by progressive dysfunction in both parameters and ultimately c ardiac failure. When the effects of endogenous catecholamines were blocked by the beta -receptor antagonist propranolol, maximal rate of contractility (dp/dt(max)) and maximal rate of relaxation (dp/dt(min)) were significantl y blunted in 2-month-old beta (1)-receptor transgenic mice. Isolated cardio myocytes from these animals displayed markedly altered calcium transients w ith significant prolongation of the intracellular calcium transient compare d with nontransgenic littermates. We determined the expression of sarcoplas mic reticulum proteins involved in calcium handling by RNase protection ass ay and by immunoblotting. Although the expression of calsequestrin, triadin , and phospholamban was not altered, we observed a progressive decrease in junctin abundance in beta (1)-receptor transgenic mice (P<0.001 TG vs. WT). Altered expression of the sarcoplasmic reticulum protein junctin may be in volved in the pathogenesis of cardiac failure after chronic stimulation of <beta>(1)-adrenergic receptors.