Journal
EMBO REPORTS
Volume 20, Issue 4, Pages -Publisher
WILEY
DOI: 10.15252/embr.201847407
Keywords
dihydrosphingosine; DNA damage; genomic instability; histone modification; transcription
Categories
Funding
- NRW Stem Cell Network Independent Group Leader Grant [3681000801, 2681101801]
- CECAD [3624720211]
- German Heart Association (DZHK) [3632009221]
- Else Kroner-Fresenius-Stiftung
- Deutsche Forschungsgemeinschaft [KU 3511/4-1]
- University of Cologne [3622801511]
- Koeln Fortune funding
- Grants4Targets initiative by Bayer AG
- Max Planck Institute for the Biology of Ageing
- NIH [R01ES027595, R03HL133720, S10OD020025]
- National Heart, Lung, and Blood Institute of the National Institutes of Health [K01HL135464]
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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.
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