Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart

Gaurav Ahuja; Deniz Bartsch; Wenjie Yao; Simon Geissen; Stefan Frank; Aitor Aguirre; Nicole Russ; Jan-Erik Messling; Joanna Dodzian; Kim A Lagerborg; Natalia Emilse Vargas; Joscha Sergej Muck; Susanne Brodesser; Stephan Baldus; Agapios Sachinidis; Juergen Hescheler; Christoph Dieterich; Aleksandra Trifunovic; Argyris Papantonis; Michael Petrascheck; Anna Klinke; Mohit Jain; Dario Riccardo Valenzano; Leo Kurian

doi:10.15252/embr.201847407

Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart

Gaurav Ahuja, Deniz Bartsch, Wenjie Yao, Simon Geissen, Stefan Frank, Aitor Aguirre, Nicole Russ, Jan-Erik Messling, Joanna Dodzian, Kim A Lagerborg, Natalia Emilse Vargas, Joscha Sergej Muck, Susanne Brodesser, Stephan Baldus, Agapios Sachinidis, Juergen Hescheler, Christoph Dieterich, Aleksandra Trifunovic, Argyris Papantonis, Michael PetrascheckAnna Klinke, Mohit Jain, Dario Riccardo Valenzano, Leo Kurian

8 Citations (Scopus)

Abstract

Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented in vivo using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health.

Original language	English
Journal	EMBO Reports
Volume	20
Issue number	4
ISSN	1469-221X
DOIs	https://doi.org/10.15252/embr.201847407
Publication status	Published - Apr 2019
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.15252/embr.201847407

https://onlinelibrary.wiley.com/doi/pdfdirect/10.15252/embr.201847407

Cite this

Ahuja, G., Bartsch, D., Yao, W., Geissen, S., Frank, S., Aguirre, A., Russ, N., Messling, J.-E., Dodzian, J., Lagerborg, K. A., Vargas, N. E., Muck, J. S., Brodesser, S., Baldus, S., Sachinidis, A., Hescheler, J., Dieterich, C., Trifunovic, A., Papantonis, A., ... Kurian, L. (2019). Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. EMBO Reports, 20(4). https://doi.org/10.15252/embr.201847407

Ahuja, G, Bartsch, D, Yao, W, Geissen, S, Frank, S, Aguirre, A, Russ, N, Messling, J-E, Dodzian, J, Lagerborg, KA, Vargas, NE, Muck, JS, Brodesser, S, Baldus, S, Sachinidis, A, Hescheler, J, Dieterich, C, Trifunovic, A, Papantonis, A, Petrascheck, M, Klinke, A, Jain, M, Valenzano, DR & Kurian, L 2019, 'Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart', EMBO Reports, vol. 20, no. 4. https://doi.org/10.15252/embr.201847407

@article{74a6adf3a1ed4436a73170c21d141034,

title = "Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart",

abstract = "Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented in vivo using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health.",

author = "Gaurav Ahuja and Deniz Bartsch and Wenjie Yao and Simon Geissen and Stefan Frank and Aitor Aguirre and Nicole Russ and Jan-Erik Messling and Joanna Dodzian and Lagerborg, {Kim A} and Vargas, {Natalia Emilse} and Muck, {Joscha Sergej} and Susanne Brodesser and Stephan Baldus and Agapios Sachinidis and Juergen Hescheler and Christoph Dieterich and Aleksandra Trifunovic and Argyris Papantonis and Michael Petrascheck and Anna Klinke and Mohit Jain and Valenzano, {Dario Riccardo} and Leo Kurian",

note = "{\textcopyright} 2019 The Authors.",

year = "2019",

month = apr,

doi = "10.15252/embr.201847407",

language = "English",

volume = "20",

journal = "EMBO Reports",

issn = "1469-221X",

publisher = "Wiley-Blackwell",

number = "4",

}

TY - JOUR

T1 - Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart

AU - Ahuja, Gaurav

AU - Bartsch, Deniz

AU - Yao, Wenjie

AU - Geissen, Simon

AU - Frank, Stefan

AU - Aguirre, Aitor

AU - Russ, Nicole

AU - Messling, Jan-Erik

AU - Dodzian, Joanna

AU - Lagerborg, Kim A

AU - Vargas, Natalia Emilse

AU - Muck, Joscha Sergej

AU - Brodesser, Susanne

AU - Baldus, Stephan

AU - Sachinidis, Agapios

AU - Hescheler, Juergen

AU - Dieterich, Christoph

AU - Trifunovic, Aleksandra

AU - Papantonis, Argyris

AU - Petrascheck, Michael

AU - Klinke, Anna

AU - Jain, Mohit

AU - Valenzano, Dario Riccardo

AU - Kurian, Leo

PY - 2019/4

Y1 - 2019/4

N2 - Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented in vivo using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health.

AB - Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented in vivo using HAT inhibitors. Together, we report an evolutionarily conserved mechanism by which increased DHS levels drive the decline in cardiac health.

U2 - 10.15252/embr.201847407

DO - 10.15252/embr.201847407

M3 - Journal article

C2 - 30886000

SN - 1469-221X

VL - 20

JO - EMBO Reports

JF - EMBO Reports

IS - 4

ER -

Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this