Targeted Disruption of NFATc3, but Not NFATc4, Reveals an Intrinsic Defect in Calcineurin-Mediated Cardiac Hypertrophic Growth

Abstract

A calcineurin-nuclear factor of activated T cells (NFAT) regulatory pathway has been implicated in the control of cardiac hypertrophy, suggesting one mechanism whereby alterations in intracellular calcium handling are linked to the expression of hypertrophy-associated genes. Although recent studies have demonstrated a necessary role for calcineurin as a mediator of cardiac hypertrophy, the potential involvement of NFAT transcription factors as downstream effectors of calcineurin signaling has not been evaluated. Accordingly, mice with targeted disruptions in NFATc3 and NFATc4 genes were characterized. Whereas the loss of NFATc4 did not compromise the ability of the myocardium to undergo hypertrophic growth, NFATc3-null mice demonstrated a significant reduction in calcineurin transgene-induced cardiac hypertrophy at 19 days, 26 days, 6 weeks, 8 weeks, and 10 weeks of age. NFATc3-null mice also demonstrated attenuated pressure overload-and angiotensin II-induced cardiac hypertrophy. These results provide genetic evidence that calcineurin-regulated responses require NFAT effectors in vivo.Cardiac hypertrophy is defined by an increase in ventricular wall thickness accompanied by an increase in cardiomyocyte cell volume. Hypertrophic enlargement is precipitated by increased workload or by decreased efficiency within the heart, conditions that are associated with hypertension, ischemic heart disease, valvular insufficiency, neuroendocrine disruptions, or intrinsic defects in contractile proteins (reviewed in reference 30). Although initially compensatory, sustained cardiac hypertrophy predisposes an individual to sudden death, arrhythmias, functional decompensation, and overt heart failure (30).Numerous regulatory pathways have been implicated in the transduction of hypertrophic signaling, linking neuroendocrine and mechanical stress stimuli to altered cardiac gene expression (reviewed in reference 40). Although numerous hypertrophic regulatory pathways have been identified, the recent characterization of the calcium-regulated phosphatase calcineurin as an important signaling factor in the heart has generated considerable interest. Transgenic mice expressing an activated form of calcineurin in the heart developed robust hypertrophy that quickly transitioned to dilation and failure (41). Subsequently, the calcineurin inhibitory drugs cyclosporine (Cs) and FK506 were shown to inhibit or attenuate cardiac hypertrophy or cardiomyopathy in most, but not all, rodent models of heart disease, suggesting a necessary regulatory role for this signaling pathway in the heart (reviewed in reference 39). More recently, transgenic mice expressing either the calcineurin inhibitory domains of Cain, AKAP79, MCIP1, or dominant-negative calcineurin were shown to have attenuated cardiac hypertrophy in response to pathophysiologic stimulation (7,52,72).Perhaps the best-characterized target of calcineurin is the nuclear factor of activated T cells (NFAT) transcription factor family. Calcineurin directly dephosphorylates NFAT transcription fa...

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

“…Vast evidence substantiates the role of calcineurin/NFAT in ventricular cardiomyocytes in hypertrophy [14,34], and in vivo studies using genetically modified mice demonstrated a necessary role for NFATc2 [16], NFATc3 [15] and NFATc4 [14] as downstream effectors of calcineurin.…”

“…NFAT signaling is established as a pathological signaling pathway in the development of cardiac hypertrophy [13][14][15][16]. However, the role of syndecan-4 and NFAT signaling in cardiac fibroblasts has not been studied.…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…NFAT transcription factors have been shown mediating cardiac hypertrophy and function as primary calcineurin effectors in the heart. 42 GSK-3b is a serine/ threonine protein kinase that mediates the addition of phosphate molecules on certain cellular substrates, counteracts the activity of calcineurin by phosphorylating NFAT and causing its nuclear export 9,10 ( Figure 1). As a result of an active GSK-3b has a negative effect on downstream signaling mechanisms pertaining to hypertrophic gene expression, it serves as a novel therapeutic approach for cardiac hypertrophy.…”

Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box m1 transcription factor

“…4). Since NFATc3 protein regulates genes essential for cardiac hypertrophy and cardiomyocyte proliferation (Wilkins et al, 2002;Sanna et al, 2005), diminished NFATc3 levels may contribute to the proliferation defects seen in Foxm1 Ϫ/Ϫ cardiomyocytes. Interestingly, we observed normal cardiac expression of calmodulin, H11 kinase, serotonin 5-HT 2B receptor, and FoxO3a transcription factor (Fig.…”