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

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

Author information

1
Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
2
Division of Cardiology, Medical University of Graz, Graz 8036, Austria.
3
Center for Biomarker Research in Medicine, CBmed GmbH, Graz 8010, Austria.
4
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz 8036, Austria.
5
Institute of Pathology, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz 8036, Austria.
6
Omics Center Graz, BioTechMed-Graz, Graz 8010, Austria.
7
CENTRe: Consortium for Environmental and Neonatal Therapeutics Research, Lewis Katz School of Medicine, Department of Physiology, Department of Thoracic Medicine and Surgery, Pediatrics, Center for Inflammation, Translational and Clinical Lung Research, Temple University, Philadelphia, PA 19140, USA.
8
Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research and Translation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
9
Department of Clinical Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
10
Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
11
Institute of Chemical Technology and Analytical Chemistry, Vienna University of Technology, Vienna 1060, Austria.
12
Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA. srhouser@temple.edu.

Abstract

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.

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