Early impairment of calcium handling and altered expression of junctin in hearts of mice overexpressing the beta1-adrenergic receptor.
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.
Engelhardt
S
S
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany; and, Institut für Pharmakologie und Toxikologie, Universität Münster, Germany.
Boknik
P
P
Keller
U
U
Neumann
J
J
Lohse
M J
MJ
Hein
L
L
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013997:Time Factors; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002352:Carrier Proteins; D008565:Membrane Proteins; D006899:Mixed Function Oxygenases; D009124:Muscle Proteins; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C498841:Asph protein, mouse; C419389:ASPH protein, human