Research ArticleCardiology

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

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Science Translational Medicine  08 Jan 2020:
Vol. 12, Issue 525, eaay7205
DOI: 10.1126/scitranslmed.aay7205

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Counteracting cardiopulmonary dysfunction

In patients with heart failure, impaired relaxation of the left ventricle (diastolic dysfunction) results in incomplete filling with blood and increased pressure. Wallner et al. treated a feline model of slow-progressive pressure-overload–induced diastolic dysfunction with the histone deacetylase inhibitor SAHA. SAHA increased myofibril relaxation, improved pulmonary function, reduced left ventricular filling pressures, and reduced left ventricle hypertrophy in cats. The authors determined that SAHA altered acetylation of mitochondrial enzymes, resulting in enhanced mitochondrial respiration. Results suggest that histone deacetylase inhibition could potentially be beneficial for improving cardiopulmonary function.

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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