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

Publication ,  Journal Article
Cho, MC; Rapacciuolo, A; Koch, WJ; Kobayashi, Y; Jones, LR; Rockman, HA
Published in: J Biol Chem
August 6, 1999

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.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 6, 1999

Volume

274

Issue

32

Start / End Page

22251 / 22256

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Systole
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phenotype
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
  • Heart Ventricles
  • Heart Function Tests
 

Citation

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Cho, M. C., Rapacciuolo, A., Koch, W. J., Kobayashi, Y., Jones, L. R., & Rockman, H. A. (1999). Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem, 274(32), 22251–22256. https://doi.org/10.1074/jbc.274.32.22251
Cho, M. C., A. Rapacciuolo, W. J. Koch, Y. Kobayashi, L. R. Jones, and H. A. Rockman. “Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression.J Biol Chem 274, no. 32 (August 6, 1999): 22251–56. https://doi.org/10.1074/jbc.274.32.22251.
Cho MC, Rapacciuolo A, Koch WJ, Kobayashi Y, Jones LR, Rockman HA. Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem. 1999 Aug 6;274(32):22251–6.
Cho, M. C., et al. “Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression.J Biol Chem, vol. 274, no. 32, Aug. 1999, pp. 22251–56. Pubmed, doi:10.1074/jbc.274.32.22251.
Cho MC, Rapacciuolo A, Koch WJ, Kobayashi Y, Jones LR, Rockman HA. Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem. 1999 Aug 6;274(32):22251–22256.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 6, 1999

Volume

274

Issue

32

Start / End Page

22251 / 22256

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Systole
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phenotype
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
  • Heart Ventricles
  • Heart Function Tests