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 Jones, Howard A. Rockman

Research output: Contribution to journalArticle

101 Citations (Scopus)

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

Fingerprint

Calsequestrin
Dilated Cardiomyopathy
Adrenergic Receptors
Transgenic Mice
Echocardiography
Ryanodine Receptor Calcium Release Channel
Premature Mortality
Sarcoplasmic Reticulum
Cardiac Catheterization
Cardiomyopathies
Adenylyl Cyclases
Muscle Cells
Hypertrophy
Carrier Proteins
Phosphotransferases
Heart Failure
Phenotype

ASJC Scopus subject areas

  • Biochemistry

Cite this

Defective β-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. / Cho, Myeong Chan; Rapacciuolo, Antonio; Koch, Walter J.; Kobayashi, Yvonne; Jones, Larry; Rockman, Howard A.

In: Journal of Biological Chemistry, Vol. 274, No. 32, 06.08.1999, p. 22251-22256.

Research output: Contribution to journalArticle

Cho, Myeong Chan ; Rapacciuolo, Antonio ; Koch, Walter J. ; Kobayashi, Yvonne ; Jones, Larry ; Rockman, Howard A. / Defective β-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 32. pp. 22251-22256.
@article{1c8eca5c389f4702989e255021d5dd48,
title = "Defective β-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression",
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.",
author = "Cho, {Myeong Chan} and Antonio Rapacciuolo and Koch, {Walter J.} and Yvonne Kobayashi and Larry Jones and Rockman, {Howard A.}",
year = "1999",
month = "8",
day = "6",
doi = "10.1074/jbc.274.32.22251",
language = "English",
volume = "274",
pages = "22251--22256",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "32",

}

TY - JOUR

T1 - Defective β-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression

AU - Cho, Myeong Chan

AU - Rapacciuolo, Antonio

AU - Koch, Walter J.

AU - Kobayashi, Yvonne

AU - Jones, Larry

AU - Rockman, Howard A.

PY - 1999/8/6

Y1 - 1999/8/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033529637&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033529637&partnerID=8YFLogxK

U2 - 10.1074/jbc.274.32.22251

DO - 10.1074/jbc.274.32.22251

M3 - Article

C2 - 10428792

AN - SCOPUS:0033529637

VL - 274

SP - 22251

EP - 22256

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 32

ER -