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Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy

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Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. / Viereck, Janika; Bührke, Anne; Foinquinos, Ariana; Chatterjee, Shambhabi; Kleeberger, Jan A; Xiao, Ke; Janssen-Peters, Heike; Batkai, Sandor; Ramanujam, Deepak; Kraft, Theresia; Cebotari, Serghei; Gueler, Faikah; Beyer, Andreas M; Schmitz, Jessica; Bräsen, Jan H; Schmitto, Jan D; Gyöngyösi, Mariann; Löser, Alexandra; Hirt, Marc N; Eschenhagen, Thomas; Engelhardt, Stefan; Bär, Christian; Thum, Thomas.

In: EUR HEART J, Vol. 41, No. 36, 21.09.2020, p. 3462-3474.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Viereck, J, Bührke, A, Foinquinos, A, Chatterjee, S, Kleeberger, JA, Xiao, K, Janssen-Peters, H, Batkai, S, Ramanujam, D, Kraft, T, Cebotari, S, Gueler, F, Beyer, AM, Schmitz, J, Bräsen, JH, Schmitto, JD, Gyöngyösi, M, Löser, A, Hirt, MN, Eschenhagen, T, Engelhardt, S, Bär, C & Thum, T 2020, 'Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy', EUR HEART J, vol. 41, no. 36, pp. 3462-3474. https://doi.org/10.1093/eurheartj/ehaa519

APA

Viereck, J., Bührke, A., Foinquinos, A., Chatterjee, S., Kleeberger, J. A., Xiao, K., Janssen-Peters, H., Batkai, S., Ramanujam, D., Kraft, T., Cebotari, S., Gueler, F., Beyer, A. M., Schmitz, J., Bräsen, J. H., Schmitto, J. D., Gyöngyösi, M., Löser, A., Hirt, M. N., ... Thum, T. (2020). Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. EUR HEART J, 41(36), 3462-3474. https://doi.org/10.1093/eurheartj/ehaa519

Vancouver

Viereck J, Bührke A, Foinquinos A, Chatterjee S, Kleeberger JA, Xiao K et al. Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. EUR HEART J. 2020 Sep 21;41(36):3462-3474. https://doi.org/10.1093/eurheartj/ehaa519

Bibtex

@article{3a976098eeee43bf99bc215da571741f,
title = "Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy",
abstract = "AIMS: Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.METHOD AND RESULTS: Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.CONCLUSION: H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.",
author = "Janika Viereck and Anne B{\"u}hrke and Ariana Foinquinos and Shambhabi Chatterjee and Kleeberger, {Jan A} and Ke Xiao and Heike Janssen-Peters and Sandor Batkai and Deepak Ramanujam and Theresia Kraft and Serghei Cebotari and Faikah Gueler and Beyer, {Andreas M} and Jessica Schmitz and Br{\"a}sen, {Jan H} and Schmitto, {Jan D} and Mariann Gy{\"o}ngy{\"o}si and Alexandra L{\"o}ser and Hirt, {Marc N} and Thomas Eschenhagen and Stefan Engelhardt and Christian B{\"a}r and Thomas Thum",
note = "{\textcopyright} The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.",
year = "2020",
month = sep,
day = "21",
doi = "10.1093/eurheartj/ehaa519",
language = "English",
volume = "41",
pages = "3462--3474",
journal = "EUR HEART J",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "36",

}

RIS

TY - JOUR

T1 - Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy

AU - Viereck, Janika

AU - Bührke, Anne

AU - Foinquinos, Ariana

AU - Chatterjee, Shambhabi

AU - Kleeberger, Jan A

AU - Xiao, Ke

AU - Janssen-Peters, Heike

AU - Batkai, Sandor

AU - Ramanujam, Deepak

AU - Kraft, Theresia

AU - Cebotari, Serghei

AU - Gueler, Faikah

AU - Beyer, Andreas M

AU - Schmitz, Jessica

AU - Bräsen, Jan H

AU - Schmitto, Jan D

AU - Gyöngyösi, Mariann

AU - Löser, Alexandra

AU - Hirt, Marc N

AU - Eschenhagen, Thomas

AU - Engelhardt, Stefan

AU - Bär, Christian

AU - Thum, Thomas

N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2020/9/21

Y1 - 2020/9/21

N2 - AIMS: Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.METHOD AND RESULTS: Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.CONCLUSION: H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

AB - AIMS: Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.METHOD AND RESULTS: Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.CONCLUSION: H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

U2 - 10.1093/eurheartj/ehaa519

DO - 10.1093/eurheartj/ehaa519

M3 - SCORING: Journal article

C2 - 32657324

VL - 41

SP - 3462

EP - 3474

JO - EUR HEART J

JF - EUR HEART J

SN - 0195-668X

IS - 36

ER -