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.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Ahuja G,Bartsch D,Yao W,Geissen S,Frank S,Aguirre A,Russ N,Messling JE,Dodzian J,Lagerborg KA,Vargas NE,Muck JS,Brodesser S,Baldus S,Sachinidis A,Hescheler J,Dieterich C,Trifunovic A,Papantonis A,Petrascheck M,Kli

doi

10.15252/embr.201847407

subject

Has Abstract

pub_date

2019-04-01 00:00:00

issue

4

eissn

1469-221X

issn

1469-3178

pii

embr.201847407

journal_volume

20

pub_type

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