Ca2+-dependent calcineurin/NFAT signaling in β-adrenergic-induced cardiac hypertrophy.

Ca2+ is an important mediator in the β-adrenergic-induced cardiac hypertrophy. The β-adrenergic stimulation alters the Ca2+ transient characteristics including its oscillation frequency, diastolic and systolic levels which lead to the CaN activation and subsequent NFAT-dependent hypertrophic genes transcription. Moreover, β-adrenergic-induced alterations in PKA and GSK3β kinase activities in both the cytosol and the nucleus regulate NFAT nuclear translocation and contribute in its hypertrophic response. Due to the complex nature of CaN/NFAT signaling in cardiac cells, we use a computational approach to investigate the β-adrenergic-induced CaN/NFAT activation in the cardiac myocytes. The presented model predicts well the main physiological characteristics of CaN/NFAT signaling in accordance with the experimental observations. The presented model establishes the previous experimental and mathematical results on the principal role of Ca2+ oscillation frequency in the CaN/NFAT signaling and shows that increase in Ca2+ oscillation frequency enhances CaN activity and its sensitivity to low ISO concentrations. The model illustrates that in addition to the known ISO effect on Ca2+ transient amplitude, ISO-induced alterations in Ca2+ oscillation frequency, PKA and GSK3β kinase activities also greatly affect the β-adrenergic-induced NFAT activity. We also found that PKA has both pro-hypertrophic and anti-hypertrophic effects on NFAT activation and is the main kinase in ISO-induced NFAT activation.