HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction

Sci Transl Med. 2020 Jan 8;12(525):eaay7205. doi: 10.1126/scitranslmed.aay7205.


Heart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration-approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) (P < 0.0001) and left atrium size (P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA (P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Cats
  • Diastole* / drug effects
  • Disease Models, Animal
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology*
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Lung / drug effects
  • Lung / pathology
  • Lung / physiopathology
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology
  • Myofibrils / drug effects
  • Myofibrils / metabolism
  • Phenotype
  • Protein Processing, Post-Translational / drug effects
  • Stroke Volume / drug effects
  • Vorinostat / pharmacology
  • Vorinostat / therapeutic use


  • Histone Deacetylase Inhibitors
  • Vorinostat