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 Repjournal_title
EMBO reportsauthors
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,Klidoi
10.15252/embr.201847407subject
Has Abstractpub_date
2019-04-01 00:00:00issue
4eissn
1469-221Xissn
1469-3178pii
embr.201847407journal_volume
20pub_type
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