Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression.
Calsequestrin is a high capacity Ca(2+)-binding protein in the junctional sarcoplasmic reticulum that forms a quaternary complex with junctin, triadin, and the ryanodine receptor. Transgenic mice with cardiac-targeted calsequestrin overexpression show marked suppression of Ca(2+)-induced Ca(2+) release, myocyte hypertrophy, and premature death by 16 weeks of age (Jones, L. R., Suzuki, Y. J., Wang, W., Kobayashi, Y. M., Ramesh, V., Franzini-Armstrong, C., Cleemann, L., and Morad, M. (1998) J. Clin. Invest. 101, 1385-1393). To investigate whether alterations in intracellular Ca(2+) trigger changes in the beta-adrenergic receptor pathway, we studied calsequestrin overexpressing transgenic mice at 7 and 14 weeks of age. As assessed by echocardiography, calsequestrin mice at 7 weeks showed mild left ventricular enlargement, mild decreased fractional shortening with increased wall thickness. By 14 weeks, the phenotype progressed to marked left ventricular enlargement and severely depressed systolic function. Cardiac catheterization in calsequestrin mice revealed markedly impaired beta-adrenergic receptor responsiveness in both 7- and 14- week mice. Biochemical analysis in 7- and 14-week mice showed a significant decrease in total beta-adrenergic receptor density, adenylyl cyclase activity, and the percent high affinity agonist binding, which was associated with increased beta-adrenergic receptor kinase 1 levels. Taken together, these data indicate that alterations in beta-adrenergic receptor signaling precede the development of overt heart failure in this mouse model of progressive cardiomyopathy.
Cho
M C
MC
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Rapacciuolo
A
A
Koch
W J
WJ
Kobayashi
Y
Y
Jones
L R
LR
Rockman
H A
HA
D000367:Age Factors; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002155:Calsequestrin / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004452:Echocardiography; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D010641:Phenotype; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D013599:Systole; D051552:beta-Adrenergic Receptor Kinases
D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases