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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.

SUBMITTER: Wallner M

PROVIDER: S-EPMC7065257 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Wallner Markus M Eaton Deborah M DM Berretta Remus M RM Liesinger Laura L Schittmayer Matthias M Gindlhuber Juergen J Wu Jichuan J Jeong Mark Y MY Lin Ying H YH Borghetti Giulia G Baker Sandy T ST Zhao Huaqing H Pfleger Jessica J Blass Sandra S Rainer Peter P PP von Lewinski Dirk D Bugger Heiko H Mohsin Sadia S Graier Wolfgang F WF Zirlik Andreas A McKinsey Timothy A TA Birner-Gruenberger Ruth R Wolfson Marla R MR Houser Steven R SR

Science translational medicine 20200101 525

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 = ...[more]

PMID: 31915304

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Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.

Project description:BackgroundDiastolic dysfunction (DD) is associated with the development of heart failure and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. We addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction.MethodsFour weeks after uninephrectomy and implantation with deoxycorticosterone acetate pellets, when DD was clearly evident, 1 cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and end point invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red staining and second harmonic generation microscopy of left ventricle (LV) sections, RNA sequencing of LV mRNA, mass spectrometry-based evaluation of decellularized LV biopsies, and atomic force microscopy determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts.ResultsHDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. In contrast to previous models, myofibril relaxation was unimpaired in uninephrectomy/deoxycorticosterone acetate mice. Furthermore, cardiac fibrosis was not evident in any mouse cohort on the basis of picrosirius red staining or second harmonic generation microscopy. However, mass spectrometry revealed induction in the expression of >100 extracellular matrix proteins in LVs of uninephrectomy/deoxycorticosterone acetate mice, which correlated with profound tissue stiffening based on atomic force microscopy. ITF2357/Givinostat treatment blocked extracellular matrix expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the profibrotic chromatin reader protein BRD4 (bromodomain-containing protein 4) to key gene regulatory elements.ConclusionsThese findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD and establish blockade of extracellular matrix remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Our data reveal the existence of pathophysiologically relevant covert or hidden cardiac fibrosis that is below the limit of detection of histochemical stains such as picrosirius red, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.

Project description:BackgroundDuring sepsis, gram-negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)-anchored receptor CD14 transferring LPS to the Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy.ObjectivesWe investigated the effect of CD14 blockade on sepsis-induced coagulopathy, inflammation, organ dysfunction, and mortality.MethodsWe used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti-CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli.ResultsFollowing anti-CD14 treatment, two animals reached the 7-day end-point survivor criteria, while three animals had a significantly prolonged survival as compared to the non-treated animals that developed multiple organ failure and died within 30 hours. Anti-CD14 reduced the activation of coagulation through inhibition of tissue factor-dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b-9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti-CD14 reduced neutrophil activation, cell death, LPS levels, and pro-inflammatory cytokines (tumor necrosis factor, interleukin (IL)-6, IL-1β, IL-8, interferon gamma, monocyte chemoattractant protein-1), more significantly in the survivors than non-surviving animals.ConclusionsOur results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti-CD14 treatment in E coli sepsis.

Project description:Despite the increasing prevalence of heart failure with preserved left ventricular function, there are no specific treatments, partially because the mechanism of impaired relaxation is incompletely understood. Evidence indicates that cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring the co-factor tetrahydrobiopterin (BH(4)). Recently, we reported that hypertension-induced diastolic dysfunction was accompanied by cardiac BH(4) depletion, NOS uncoupling, a depression in myofilament cross-bridge kinetics, and S-glutathionylation of myosin binding protein C (MyBP-C). We hypothesized that the mechanism by which BH(4) ameliorates diastolic dysfunction is by preventing glutathionylation of MyBP-C and thus reversing changes of myofilament properties that occur during diastolic dysfunction. We used the deoxycorticosterone acetate (DOCA)-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction. Mice were divided into two groups that received control diet and two groups that received BH(4) supplement for 7days after developing diastolic dysfunction at post-operative day 11. Mice were assessed by echocardiography. Left ventricular papillary detergent-extracted fiber bundles were isolated for simultaneous determination of force and ATPase activity. Sarcomeric protein glutathionylation was assessed by immunoblotting. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH(4) treatment. Diastolic sarcomere length (DOCA-salt 1.70±0.01 vs. DOCA-salt+BH(4) 1.77±0.01μm, P<0.001) and relengthening (relaxation constant, τ, DOCA-salt 0.28±0.02 vs. DOCA-salt+BH(4) 0.08±0.01, P<0.001) were also restored to control by BH(4) treatment. pCa(50) for tension increased in DOCA-salt compared to sham but reverted to sham levels after BH(4) treatment. Maximum ATPase rate and tension cost (ΔATPase/ΔTension) decreased in DOCA-salt compared to sham, but increased after BH(4) treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH(4) treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH(4) ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins.

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

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

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