Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism
AuthorJeong, Mark Y.
Lin, Ying H.
Wennersten, Sara A.
Demos-Davies, Kimberly M.
Cavasin, Maria A.
Mahaffey, Jennifer H.
Reece, T. Brett
Ambardekar, Amrut V.
Granzier, Henk L.
Dinarello, Charles A.
McKinsey, Timothy A.
AffiliationUniv Arizona, Dept Cellular & Mol Med
Univ Arizona, Sarver Mol Cardiovasc Res Program
MetadataShow full item record
PublisherAMER ASSOC ADVANCEMENT SCIENCE
CitationJeong, M. Y., Lin, Y. H., Wennersten, S. A., Demos-Davies, K. M., Cavasin, M. A., Mahaffey, J. H., ... & Ambardekar, A. V. (2018). Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Science translational medicine, 10(427), eaao0144, DOI: 10.1126/scitranslmed.aao0144
JournalSCIENCE TRANSLATIONAL MEDICINE
RightsCopyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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AbstractThere are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor-mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.
VersionFinal accepted manuscript
SponsorsUCD Colorado Clinical and Translational Sciences Institute [5KL2TR001080-02]; Hartford/Jahnigen Center of Excellence in Geriatrics Pilot Grant; Sarnoff Endowment Fellow-to-Faculty Transition Award; American Heart Association postdoctoral fellowship [16POST30960017]; Scientist Development Grant from the American Heart Association; Boettcher Foundation's Webb-Waring Biomedical Research Program; NIH [5KL2TR001080-02, R01HL115988, HL116848, HL127240, AG043822]; American Heart Association [16SFRN31400013]; NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Award [UL1 TR001082]