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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009, 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
• Subjects: animal disease models; arrhythmia; calcium; calcium signaling; cardiac output; cardiomyocytes; cardiomyopathy; cytosol; endothelins; heart failure; hypertension; hypertrophy; inositols; mice; patients; rats; ryanodine receptors; sarcoplasmic reticulum
• ISSN: 0027-8424; 1091-6490

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 (InsP₃Rs) 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 InsP₃ or endothelin-1 (ET-1). Responsible for this is an increase in InsP₃R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca²⁺ release through InsP₃Rs 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 InsP₃R expression and Ca²⁺ transient amplitude in the cytosol, InsP₃R expression and ECC-mediated Ca²⁺ transients in the nucleus were not altered during hypertrophy. Elevated InsP₃R2 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 InsP₃R expression is a general mechanism that underlies remodeling of Ca²⁺ signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.