A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy

Abstract

In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. We show that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of calcineurin activity blocks hypertrophy in vivo and in vitro. These results define a novel hypertrophic signaling pathway and suggest pharmacologic approaches to prevent cardiac hypertrophy and heart failure.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…The end product is enhanced activity of kinases and phosphatases, such as calcineurin,34, 35 protein kinase A36 (activated initially with later decreases in activity) and C,37 calcium‐calmodulin‐dependent kinase II38, 39 and the mitogen‐activated protein kinases 12. Calcineurin dephosphorylates the nuclear factor of activated T cells, which then translocates to the nucleus, interacts with the cardiac zinc finger transcription factor (GATA4),34 and orchestrates the reactivation of fetal genes such as natriuretic peptides and alpha‐skeletal muscle actin, which were increased in all phenotypes here. Calcineurin also activates protein kinase C,40 and activated protein kinase C in cardiac stress37 phosphorylates and inhibits inhibitor 1, leading to phospholamban dephosphorylation and inhibition of SERCA2a activity.…”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…GATA4 is phosphorylated at Ser105 by both ERK and p38,21, 22, 23 regulating its DNA‐binding activity and transcriptional activity 22, 23, 24, 25, 26. In addition to GATA4, a number of other transcriptional regulators, such as nuclear factor of activated T‐cells (NFAT), NKX‐2.5, Elk‐1, activator protein 1, myocardin, serum response factor, and nuclear factor kappa B, have been shown to participate in transcriptional regulation of BNP 20, 27, 28, 29, 30, 31, 32. Several studies have also indicated a central role for M‐CAT element, a thyroid‐responsive element and shear stress‐responsive element on the BNP promoter regulating BNP transcriptional activity 33, 34, 35, 36.…”

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation

“…In the nucleus, NFAT family members associate with other nuclear transcription factors (e.g. JUN, GATA4, IRF, C/EBP) depending on the cell type, to mediate transcription of specific genes including cytokine and cytokine receptor genes [15][16][17]. In addition to the regulation of their nuclear localisation by phosphorylation/dephosphorylation, NFAT members can also be regulated at the level of gene expression.…”