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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., Jiang, N., May, H.I., Luo, X., Ferdous, A., Schiattarella, G.G., Chen, G., Li, Q., Li, C., Rothermel, B.A., Jiang, D., Lavandero, S., 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, Rats |
| Source: | Circulation |
| ISSN: | 0009-7322 |
| Publisher: | American Heart Association |
| Volume: | 144 |
| Number: | 1 |
| 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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