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Cooperative binding of ETS2 and NFAT link Erk1/2 and calcineurin signaling in the pathogenesis of cardiac hypertrophy

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Item Type:Article
Title:Cooperative binding of ETS2 and NFAT link Erk1/2 and calcineurin signaling in the pathogenesis of cardiac hypertrophy
Creators Name:Luo, Y. and Jiang, N. and May, H.I. and Luo, X. and Ferdous, A. and Schiattarella, G.G. and Chen, G. and Li, Q. and Li, C. and Rothermel, B.A. and Jiang, D. and Lavandero, S. and Gillette, T.G. and Hill, J.A.
Abstract:BACKGROUND: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an inter-dependent network of signaling cascades. However, how these pathways interact remains unclear, and specifically few direct targets responsible for the pro-hypertrophic role of NFAT have been described. METHODS: By engineering a cardiomyocyte-specific ETS2 (a member of E26 transformationspecific sequence (ETS)-domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. RESULTS: ETS2 is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation in both mouse (n = 3) and human heart samples (n = 8-19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n = 6-11). Furthermore, silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n = 8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP and Rcan1.4 (n = 4). Additionally, we report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least two hypertrophy-stimulated genes, Rcan1.4 and miR-223 (n = 4-6). Suppression of miR-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n = 6), revealing miR-223 as a novel pro-hypertrophic target of the calcineurin-NFAT and Erk1/2-ETS2 pathways. CONCLUSIONS: In aggregate, our findings point to a critical role for ETS2 in calcineurin-NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.
Keywords:Cardiac Hypertrophy, ETS2, Calcineurin-NFAT Pathway, MAPK/Erk Pathway, miR-223, Animals, Mice
Publisher:American Heart Association
Page Range:34-51
Date:6 July 2021
Official Publication:https://doi.org/10.1161/CIRCULATIONAHA.120.052384
PubMed:View item in PubMed

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