Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

Mark Y. Jeong, Ying H. Lin, Sara A. Wennersten, Kimberly M. Demos-Davies, Maria A. Cavasin, Jennifer H. Mahaffey, Valmen Monzani, Chandrasekhar Saripalli, Paolo Mascagni, T. Brett Reece, Amrut V. Ambardekar, Hendrikus "Henk" Granzier, Charles A. Dinarello, Timothy A. McKinsey

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

There 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.

Original languageEnglish (US)
Article numbereaao0144
JournalScience Translational Medicine
Volume10
Issue number427
DOIs
StatePublished - Feb 7 2018

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Histone Deacetylase Inhibitors
Histone Deacetylases
Myofibrils
Left Ventricular Dysfunction
Treatment Failure
Heart Failure
Inbred Dahl Rats
Cardiac Myosins
Connectin
Cardiomegaly
Muscle Cells
Protein Isoforms
Fibrosis
Blood Pressure
Hypertension
Pharmaceutical Preparations
givinostat hydrochloride

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jeong, M. Y., Lin, Y. H., Wennersten, S. A., Demos-Davies, K. M., Cavasin, M. A., Mahaffey, J. H., ... McKinsey, T. A. (2018). Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Science Translational Medicine, 10(427), [eaao0144]. https://doi.org/10.1126/scitranslmed.aao0144

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. / Jeong, Mark Y.; Lin, Ying H.; Wennersten, Sara A.; Demos-Davies, Kimberly M.; Cavasin, Maria A.; Mahaffey, Jennifer H.; Monzani, Valmen; Saripalli, Chandrasekhar; Mascagni, Paolo; Reece, T. Brett; Ambardekar, Amrut V.; Granzier, Hendrikus "Henk"; Dinarello, Charles A.; McKinsey, Timothy A.

In: Science Translational Medicine, Vol. 10, No. 427, eaao0144, 07.02.2018.

Research output: Contribution to journalArticle

Jeong, MY, Lin, YH, Wennersten, SA, Demos-Davies, KM, Cavasin, MA, Mahaffey, JH, Monzani, V, Saripalli, C, Mascagni, P, Reece, TB, Ambardekar, AV, Granzier, HH, Dinarello, CA & McKinsey, TA 2018, 'Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism', Science Translational Medicine, vol. 10, no. 427, eaao0144. https://doi.org/10.1126/scitranslmed.aao0144
Jeong MY, Lin YH, Wennersten SA, Demos-Davies KM, Cavasin MA, Mahaffey JH et al. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Science Translational Medicine. 2018 Feb 7;10(427). eaao0144. https://doi.org/10.1126/scitranslmed.aao0144
Jeong, Mark Y. ; Lin, Ying H. ; Wennersten, Sara A. ; Demos-Davies, Kimberly M. ; Cavasin, Maria A. ; Mahaffey, Jennifer H. ; Monzani, Valmen ; Saripalli, Chandrasekhar ; Mascagni, Paolo ; Reece, T. Brett ; Ambardekar, Amrut V. ; Granzier, Hendrikus "Henk" ; Dinarello, Charles A. ; McKinsey, Timothy A. / Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. In: Science Translational Medicine. 2018 ; Vol. 10, No. 427.
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