Increased InsP 3 Rs in the junctional sarcoplasmic reticulum augment Ca 2+ transients and arrhythmias associated with cardiac hypertrophy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-07, Vol.106 (27), p.11406-11411
• Main Authors: Harzheim, Dagmar, Movassagh, Mehregan, Foo, Roger S.-Y., Ritter, Oliver, Tashfeen, Aslam, Conway, Stuart J., Bootman, Martin D., Roderick, H. Llewelyn
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0905485106

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.