Increased InsP(3)Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy

Dagmar Harzheim, Mehregan Movassagh, Roger S. -Y. Foo, Oliver Ritter, Tashfeen Aslam, Stuart J. Conway, Martin D. Bootman, H. Llewelyn Roderick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

Abstract

Cardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca2+ signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca2+ fluxes significantly impact on cardiac output and facilitate the development of arrhythmias. Using cardiomyocytes from spontaneously hypertensive rats (SHRs), we demonstrate that an increase in Ca2+ release through inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) contributes to the larger excitation contraction coupling (ECC)- mediated Ca2+ transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECC-mediated Ca2+ transients and contraction elicited by InsP(3) or endothelin-1 (ET-1). Responsible for this is an increase in InsP(3)R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca2+ release through InsP(3)Rs served to sensitize RyRs, thereby increasing diastolic Ca2+ levels, the incidence of extra-systolic Ca2+ transients, and the induction of ECC-mediated Ca2+ elevations. Unlike the increase in InsP(3)R expression and Ca2+ transient amplitude in the cytosol, InsP(3)R expression and ECC-mediated Ca2+ transients in the nucleus were not altered during hypertrophy. Elevated InsP(3)R2 expression was also detected in hearts from human patients with heart failure after ischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophic mouse hearts. Our data establish that increased InsP(3)R expression is a general mechanism that underlies remodeling of Ca2+ signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.

Original languageEnglish
Pages (from-to)11406-11411
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number27
DOIs
Publication statusPublished - 7 Jul 2009

Keywords

  • calcium
  • ECC
  • IP3
  • SHR
  • signalling
  • LEFT-VENTRICULAR HYPERTROPHY
  • SPONTANEOUSLY HYPERTENSIVE-RAT
  • INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR
  • ATRIAL MYOCYTES
  • CALCIUM-RELEASE
  • HEART-FAILURE
  • ENDOTHELIN-1
  • FIBRILLATION
  • INOSITOL-1,4,5-TRISPHOSPHATE
  • CONTRACTILITY

Fingerprint

Dive into the research topics of 'Increased InsP(3)Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy'. Together they form a unique fingerprint.

Cite this