Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction

D. Julia Trembinski; Diewertje I. Bink; Kosta Theodorou; Janina Sommer; Ariane Fischer; Anke van Bergen; Chao Chung Kuo; Ivan G. Costa; Christoph Schürmann; Matthias S. Leisegang; Ralf P. Brandes; Tijna Alekseeva; Boris Brill; Astrid Wietelmann; Christopher N. Johnson; Alexander Spring-Connell; Manuel Kaulich; Stanislas Werfel; Stefan Engelhardt; Marc N. Hirt; Kaja Yorgan; Thomas Eschenhagen; Luisa Kirchhof; Patrick Hofmann; Nicolas Jaé; Ilka Wittig; Nazha Hamdani; Corinne Bischof; Jaya Krishnan; Riekelt H. Houtkooper; Stefanie Dimmeler; Reinier A. Boon

doi:10.1038/s41467-020-15995-2

Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction

D. Julia Trembinski, Diewertje I. Bink, Kosta Theodorou, Janina Sommer, Ariane Fischer, Anke van Bergen, Chao Chung Kuo, Ivan G. Costa, Christoph Schürmann, Matthias S. Leisegang, Ralf P. Brandes, Tijna Alekseeva, Boris Brill, Astrid Wietelmann, Christopher N. Johnson, Alexander Spring-Connell, Manuel Kaulich, Stanislas Werfel, Stefan Engelhardt, Marc N. HirtKaja Yorgan, Thomas Eschenhagen, Luisa Kirchhof, Patrick Hofmann, Nicolas Jaé, Ilka Wittig, Nazha Hamdani, Corinne Bischof, Jaya Krishnan, Riekelt H. Houtkooper, Stefanie Dimmeler, Reinier A. Boon

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Abstract

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.

Original language	English
Article number	2039
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15995-2
State	Published - 1 Dec 2020

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Trembinski, D. J., Bink, D. I., Theodorou, K., Sommer, J., Fischer, A., van Bergen, A., Kuo, C. C., Costa, I. G., Schürmann, C., Leisegang, M. S., Brandes, R. P., Alekseeva, T., Brill, B., Wietelmann, A., Johnson, C. N., Spring-Connell, A., Kaulich, M., Werfel, S., Engelhardt, S., ... Boon, R. A. (2020). Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction. Nature Communications, 11(1), Article 2039. https://doi.org/10.1038/s41467-020-15995-2

@article{751266725fb14bddbfe9027634760557,

title = "Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction",

abstract = "Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.",

author = "Trembinski, {D. Julia} and Bink, {Diewertje I.} and Kosta Theodorou and Janina Sommer and Ariane Fischer and {van Bergen}, Anke and Kuo, {Chao Chung} and Costa, {Ivan G.} and Christoph Sch{\"u}rmann and Leisegang, {Matthias S.} and Brandes, {Ralf P.} and Tijna Alekseeva and Boris Brill and Astrid Wietelmann and Johnson, {Christopher N.} and Alexander Spring-Connell and Manuel Kaulich and Stanislas Werfel and Stefan Engelhardt and Hirt, {Marc N.} and Kaja Yorgan and Thomas Eschenhagen and Luisa Kirchhof and Patrick Hofmann and Nicolas Ja{\'e} and Ilka Wittig and Nazha Hamdani and Corinne Bischof and Jaya Krishnan and Houtkooper, {Riekelt H.} and Stefanie Dimmeler and Boon, {Reinier A.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-15995-2",

language = "English",

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Trembinski, DJ, Bink, DI, Theodorou, K, Sommer, J, Fischer, A, van Bergen, A, Kuo, CC, Costa, IG, Schürmann, C, Leisegang, MS, Brandes, RP, Alekseeva, T, Brill, B, Wietelmann, A, Johnson, CN, Spring-Connell, A, Kaulich, M, Werfel, S, Engelhardt, S, Hirt, MN, Yorgan, K, Eschenhagen, T, Kirchhof, L, Hofmann, P, Jaé, N, Wittig, I, Hamdani, N, Bischof, C, Krishnan, J, Houtkooper, RH, Dimmeler, S & Boon, RA 2020, 'Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction', Nature Communications, vol. 11, no. 1, 2039. https://doi.org/10.1038/s41467-020-15995-2

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T1 - Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction

AU - Trembinski, D. Julia

AU - Bink, Diewertje I.

AU - Theodorou, Kosta

AU - Sommer, Janina

AU - Fischer, Ariane

AU - van Bergen, Anke

AU - Kuo, Chao Chung

AU - Costa, Ivan G.

AU - Schürmann, Christoph

AU - Leisegang, Matthias S.

AU - Brandes, Ralf P.

AU - Alekseeva, Tijna

AU - Brill, Boris

AU - Wietelmann, Astrid

AU - Johnson, Christopher N.

AU - Spring-Connell, Alexander

AU - Kaulich, Manuel

AU - Werfel, Stanislas

AU - Engelhardt, Stefan

AU - Hirt, Marc N.

AU - Yorgan, Kaja

AU - Eschenhagen, Thomas

AU - Kirchhof, Luisa

AU - Hofmann, Patrick

AU - Jaé, Nicolas

AU - Wittig, Ilka

AU - Hamdani, Nazha

AU - Bischof, Corinne

AU - Krishnan, Jaya

AU - Houtkooper, Riekelt H.

AU - Dimmeler, Stefanie

AU - Boon, Reinier A.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.

AB - Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.

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DO - 10.1038/s41467-020-15995-2

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JO - Nature Communications

JF - Nature Communications

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ER -

Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction

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