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

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.

Alteration of m6A RNA Methylation in Heart Failure With Preserved Ejection Fraction

“…Moreover, the alteration of microRNAs, such as down-regulation of miRNA-1 and up-regulation of miRNA-195, controls cardiac hypertrophy, oxidative stress, ischemic susceptibility, and fibrosis in HFpEF through histone modification ( 3 , 6 ). Recently, Wallner et al ( 7 ) reported that inhibition of histone deacetylases (HDAC) activity with suberoylanilide hydroxamic acid improves cardiopulmonary function, i.e., preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels in HFpEF. Furthermore, Jeong et al ( 8 ) found that HDAC inhibition with ITF2357 (givinostat) ameliorates the impairment of cardiac myofibril relaxation, cardiac fibrosis, and cardiac hypertrophy and changes in cardiac titin and myosin isoform expression in Dahl salt-sensitive rats with HFpEF, indicating that epigenetic regulation also significantly contributes to HFpEF.…”

Epigenetic gene expression links heart failure to memory impairment

“…ª 2021 The Authors EMBO Molecular Medicine 13: e11900 | 2021 note that HDAC inhibitors have been suggested as drugs to treat cardiac diseases (McKinsey, 2012), and Vorinostat was found to improve cardiac function, for example, in models for HF with preserved ejection fraction (Wallner et al, 2018) or MI (Nagata et al, 2019). However, either higher concentrations or longer treatment durations were applied in these studies.…”

Decoding empagliflozin’s molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence

“…Third, functional blockage of NHE1 also prevents activation of the NFAT1/NFAT2/NFAT3 pathway, which would result in the induction of NOS2 expression and nitric oxide production through activation of interleukin-10 (IL-10) 21 , 22 . Finally, NHE1 inhibition also interrupts the activation of HDAC1 (histone deacetylase 1) by NFκB (nuclear factor κ B) downstream of AKT, thus further reducing the oxidative stress produced by HDAC1-mediated acetylation defects 23 , 24 .…”