Parsing good versus bad signaling pathways in the heart: role of calcineurin-nuclear factor of activated T-cells

Abstract

Nine years ago, we published an article that suggested a specialized role for calcineurin–nuclear factor of activated T-cells (NFAT) signaling in regulating pathological cardiac hypertrophy preferentially over physiological growth and, in fact, the later response was associated with reduced calcineurin-NFAT activity. Since this time we and others have continued to uncover how this signaling effector pathway functions in the heart in regulating specific aspects of the growth response during disease and with exercise.

Figure 1. Calcineurin/NFAT signaling participates in pathological hypertrophy but not physiologic hypertrophy

While physiologic cardiac hypertrophy can be induced by various stimuli such as insulin-like growth factor 1 (IGF-1), which activates phosphoinositide 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) signaling effectors, pathologic hypertrophy can be triggered by the activation of the mitogen-activated protein kinases (MAPK) c-Jun N-terminal kinase (JNK) or p38 kinase and the Ca²⁺-calmodulin-activated phosphatase calcineurin. Sustained Ca²⁺ elevations leads to calcineurin activation as a heterotrimeric complex composed of calcineurin B (CnB), calmodulin (CaM) and the catalytic subunit calcineurin A (CnA). Calcineurin then dephosphorylates the nuclear factor of activated T-cells (NFAT) transcription factor in the cytosol allowing its translocation to the nucleus and induction of genes underlying pathologic cardiac hypertrophy. However, more recent genetic approaches in the mouse also show some adaptive or physiologic functions of calcineurin in permitting myocyte proliferation and protection from cell death. Finally, physiologic exercise stimulation down-regulates calcineurin/NFAT signaling, coincident with a lack of fetal gene induction despite mild hypertrophic growth of the heart.