Defective β-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression

Myeong Chan Cho, Antonio Rapacciuolo, Walter J. Koch, Yvonne Kobayashi, Larry R. Jones, Howard A. Rockman

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Calsequestrin is a high capacity Ca2+-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 Ca2+- induced Ca2+ 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 Ca2+ trigger changes in the β-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 β- adrenergic receptor responsiveness in both 7-and 14- week mice. Biochemical analysis in 7- and 14-week mice showed a significant decrease in total β- adrenergic receptor density, adenylyl cyclase activity, and the percent high affinity agonist binding, which was associated with increased β-adrenergic receptor kinase 1 levels. Taken together, these data indicate that alterations in β-adrenergic receptor signaling precede the development of overt heart failure in this mouse model of progressive cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)22251-22256
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number32
DOIs
StatePublished - Aug 6 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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