期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 10, 期 427, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aao0144
关键词
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资金
- UCD 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]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001082, KL2TR001080] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL062881, R01HL116848, R01HL115988, R01HL118524, R01HL127240] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI015614] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R21AG043822] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD018156] Funding Source: NIH RePORTER
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.
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