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

Proc Natl Acad Sci U S A. 2009 Jun 23; Harzheim D, Movassagh M, Foo RS, Ritter O, Tashfeen A, Conway SJ, Bootman MD, Roderick HLCardiac 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.