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

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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 & 4 others Anna Klinke, Mohit Jain, Dario Riccardo Valenzano, Leo Kurian

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 languageEnglish
JournalEMBO Reports
Volume20
Issue number4
ISSN1469-221X
DOIs
Publication statusPublished - Apr 2019
Externally publishedYes

Bibliographical note

© 2019 The Authors.

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