Ahuja, Gaurav ORCID: 0000-0002-2837-9361, Bartsch, Deniz, Yao, Wenjie, Geissen, Simon, Frank, Stefan, Aguirre, Aitor ORCID: 0000-0002-1383-2792, Russ, Nicole, Messling, Jan-Erik ORCID: 0000-0003-3843-0041, 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 ORCID: 0000-0001-7551-1073, Petrascheck, Michael, Klinke, Anna, Jain, Mohit, Valenzano, Dario Riccardo and Kurian, Leo ORCID: 0000-0001-7466-5169 (2019). Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. EMBO Rep., 20 (4). HOBOKEN: WILEY. ISSN 1469-3178

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ahuja, GauravUNSPECIFIEDorcid.org/0000-0002-2837-9361UNSPECIFIED
Bartsch, DenizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yao, WenjieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geissen, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frank, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguirre, AitorUNSPECIFIEDorcid.org/0000-0002-1383-2792UNSPECIFIED
Russ, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Messling, Jan-ErikUNSPECIFIEDorcid.org/0000-0003-3843-0041UNSPECIFIED
Dodzian, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagerborg, Kim A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vargas, Natalia EmilseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muck, Joscha SergejUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodesser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sachinidis, AgapiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hescheler, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieterich, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papantonis, ArgyrisUNSPECIFIEDorcid.org/0000-0001-7551-1073UNSPECIFIED
Petrascheck, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jain, MohitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valenzano, Dario RiccardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurian, LeoUNSPECIFIEDorcid.org/0000-0001-7466-5169UNSPECIFIED
URN: urn:nbn:de:hbz:38-152338
DOI: 10.15252/embr.201847407
Journal or Publication Title: EMBO Rep.
Volume: 20
Number: 4
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1469-3178
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COLON-CANCER; HISTONE ACETYLATION; DNA-DAMAGE; SPHINGOSINE; INHIBITOR; APOPTOSIS; TRANSCRIPTION; SENESCENCE; INDUCTION; MECHANISMMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15233

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