The Open UniversitySkip to content
 

Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy

Harzheim, Dagmar; Movassagh, Mehregan; Foo, Roger S-Y; Ritter, Oliver; Tashfeen, Aslam; Conway, Stuart J.; Bootman, Martin D. and Roderick, H. Llewelyn (2009). Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 106(27) pp. 11406–11411.

Full text available as:
Full text not publicly available
Due to copyright restrictions, this file is not available for public download
Click here to request a copy from the OU Author.
DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1073/pnas.0905485106
Google Scholar: Look up in Google Scholar

Abstract

Cardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca(2+) signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca(2+) 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 Ca(2+) release through inositol 1,4,5-trisphosphate receptors (InsP(3)Rs) contributes to the larger excitation contraction coupling (ECC)-mediated Ca(2+) transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECC-mediated Ca(2+) 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 Ca(2+) release through InsP(3)Rs served to sensitize RyRs, thereby increasing diastolic Ca(2+) levels, the incidence of extra-systolic Ca(2+) transients, and the induction of ECC-mediated Ca(2+) elevations. Unlike the increase in InsP(3)R expression and Ca(2+) transient amplitude in the cytosol, InsP(3)R expression and ECC-mediated Ca(2+) 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 Ca(2+) signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.

Item Type: Journal Article
Copyright Holders: 2009 National Academy of Sciences
ISSN: 1091-6490
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 34862
Depositing User: Martin Bootman
Date Deposited: 20 Nov 2012 11:50
Last Modified: 07 Mar 2014 23:07
URI: http://oro.open.ac.uk/id/eprint/34862
Share this page:

Altmetrics

Scopus Citations

Actions (login may be required)

View Item
Report issue / request change

Policies | Disclaimer

© The Open University   + 44 (0)870 333 4340   general-enquiries@open.ac.uk