Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. (18th March 2019)

• Record Type: Journal Article
• Authors: Ahuja, Gaurav; Bartsch, Deniz; Yao, Wenjie; Geissen, Simon; Frank, Stefan; Aguirre, Aitor; Russ, Nicole; Messling, Jan‐Erik; Dodzian, Joanna; Lagerborg, Kim A; Vargas, Natalia Emilse; Muck, Joscha Sergej; Brodesser, Susanne; Baldus, Stephan; Sachinidis, Agapios; Hescheler, Juergen; Dieterich, Christoph; Trifunovic, Aleksandra; Papantonis, Argyris; Petrascheck, Michael; Klinke, Anna; Jain, Mohit; Valenzano, Dario Riccardo; Kurian, Leo
• Is Part Of: EMBO reports. Volume 20:Number 4(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-03-18
• Subjects: dihydrosphingosine -- DNA damage -- genomic instability -- histone modification -- transcription; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201847407
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: The metabolite dihydrosphingosine (DHS), a potent HDAC inhibitor, accumulates in the heart in an age‐dependent manner. Elevated DHS levels result in cellular transcription‐dependent DNA damage, which ultimately causes ageing‐associated cardiac insufficiencies. Elevated sphinganine (DHS) levels is an evolutionarily conserved hallmark of cardiac ageing, including humans. Elevated DHS levels cause DNA damage in cardiomyocytes in vitro and in vivo . DHS derivative DHS1P is a potent HDAC inhibitor causing histone hyperacetylation and increased transcription, leading to DNA damage. Exogenous increase of DHS levels in young adult mice causes ageing‐associated functional impairment of the heart. Restoring histone acetylation levels by HAT inhibition prevents DHS‐induced cardiac DNA damage and functional impairment in vivo . Abstract : The metabolite dihydrosphingosine (DHS), a potent HDAC inhibitor, accumulates in the heart in an age‐dependent manner. Elevated DHS levels result in cellular transcription‐dependent DNA damage, which ultimately causes ageing‐associated cardiac insufficiencies.