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

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 3Rs) contributes to the larger excitation contraction coupling (ECC)-mediated Ca 2؉ transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECCmediated Ca 2؉ transients and contraction elicited by InsP3 or endothelin-1 (ET-1). Responsible for this is an increase in InsP 3R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca 2؉ release through InsP 3Rs 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 3R expression and Ca 2؉ transient amplitude in the cytosol, InsP3R expression and ECC-mediated Ca 2؉ transients in the nucleus were not altered during hypertrophy. Elevated InsP 3R2 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 3R expression is a general mechanism that underlies remodeling of Ca 2؉ signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.calcium ͉ ECC ͉ IP3 ͉ SHR ͉ signalling

Elevated InsP3R expression underlies enhanced calcium fluxes and spontaneous extra-systolic calcium release events in hypertrophic cardiac myocytes

“…31 However, our results show that the increase in InsP 3 R expression seems to be independent of how hypertrophy has been induced. 15 Considering the pro-arrhythmic effect of increased InsP 3 R expression, which is clearly evident in our study, this raises the question of why InsP 3 R expression is enhanced in hypertrophic and failing cardiomyocytes? During hypertrophy a decrease in the coupling efficiency arrhythmias associated with hypertrophy and heart failure.…”

“…In a recent study, 15 we established that augmented expression and Ca 2+ release through InsP 3 Rs contribute to enhanced Ca 2+ fluxes and increased spontaneous arrhythmogenic Ca 2+ events associated with hypertrophy. As a model to study hypertrophy-dependent changes in Ca 2+ signaling, we used hypertrophic ventricular cardiomyocytes from spontaneously hypertensive rats (SHR) and non-hypertrophic ventricular cardiomyocytes from Wistar Kyoto rats (WKY) as controls.…”

Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways

“…Changes in calcium handling in cardiomyocytes have been linked to a number of cardiac disorders (16,(32)(33)(34)(35), including CPVT (36,37). We have previously demonstrated that PC2 interacts with and can regulate the RyR2 by acting as a brake on calcium release, and that total loss of PC2 results in a slow but uncontrolled release of calcium through the RyR2 (19).…”

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“…In recent years, however, it has been found that leakage from the sarcoplasmic reticulum may also take place «silently», independently of RyR (25). It is conceivable that such leakage could take place through IP 3 R. It is therefore very interesting that heart failure, the end-point of many heart diseases, is associated with an increased amount of IP 3 R in the heart (22,26).…”