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

摘要

Cardiac hypertrophy is associated with profound remodelling of Ca~(2+) signalling pathways. During the early, compensated stages of hypertrophy, Ca~(2+ )fluxes may be enhanced to facilitate greater contraction, whereas as the hypertrophic heart decompensates, Ca~(2+) homeostatic mechanisms are dysregulated leading to decreased contractility, arrhythmia and death. Although ryanodine receptor Ca~(2+) release channels (RyR) on the sarcoplasmic reticulum (SR) intracellular Ca~(2+) store are primarily responsible for the Ca~(2+) flux that induces myocyte contraction, a role for Ca~(2+) release via the inositol 1,4,5-trisphosphate receptor (InsP_(3)R) in cardiac physiology has also emerged. Specifically, InsP_(3)-induced Ca~(2+) signals generated following myocyte stimulation with an InsP_(3)-generating agonist (e.g. endothelin, ET-1), lead to modulation of Ca~(2+) signals associated with excitation-contraction coupling (ECC) and the induction of spontaneous Ca~(2+) release events that cause cellular arrhythmia. Using myocytes from spontaneously hypertensive rats (SHR), we recently reported that expression of the type 2 InsP_(3)R (InsP_(3)R2) is significantly increased during hypertrophy. Notably, this increased expression was restricted to the junctional SR in close proximity to RyRs. There, enhanced Ca~(2+) release via InsP_(3)Rs serves to sensitise neighbouring RyRs causing an augmentation of Ca~(2+) fluxes during ECC as well as an increase in non-triggered Ca~(2+) release events. Although the sensitization of RyRs may be a beneficial consequence of elevated InsP_(3)R expression during hypertrophy, the spontaneous Ca~(2+) release events are potentially of pathological significance giving rise to cardiac arrhythmia. InsP_(3)R2 expression was also increased in hypertrophic hearts from patients with ischemic dilated cardiomyopathy and aortically-banded mice demonstrating that increased InsP_(3)R expression may be a general phenomenon that underlies Ca~(2+) changes during hypertrophy.