PXD013663-2

PXD013663 is an original dataset announced via ProteomeXchange.

Title	HDAC inhibition improves cardiopulmonary and mitochondrial function in a feline model with features of Heart Failure with Preserved Ejection Fraction
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:26:13.812.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Barbara Darnhofer
SpeciesList	scientific name: Felis catus (Cat) (Felis silvestris catus); NCBI TaxID: 9685;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	maXis

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-30 02:36:36	ID requested
1	2021-09-08 10:17:47	announced
⏵ 2	2024-10-22 05:26:18	announced	2024-10-22: Updated project metadata.

10.1126/scitranslmed.aay7205;

Wallner M, Eaton DM, Berretta RM, Liesinger L, Schittmayer M, Gindlhuber J, Wu J, Jeong MY, Lin YH, Borghetti G, Baker ST, Zhao H, Pfleger J, Blass S, Rainer PP, von Lewinski D, Bugger H, Mohsin S, Graier WF, Zirlik A, McKinsey TA, Birner-Gruenberger R, Wolfson MR, Houser SR, HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci Transl Med, 12(525):(2020) [pubmed]

submitter keyword: myofibril relaxation, hypertrophy,Cat, HDAC, heart failure, Acetylation proteomics, pulmonary hypertension, lung compliance

Ruth Birner-Gruenberger
contact affiliation	Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria; Institute of Pathology, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria; Omics Center Graz, BioTechMed-Graz, Graz, Austria
contact email	ruth.birner-gruenberger@medunigraz.at
lab head
Barbara Darnhofer
contact affiliation	Omics Center Graz
contact email	barbara.darnhofer@klinikum-graz.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013663
     1. Label: PRIDE project
     2. Name: HDAC inhibition improves cardiopulmonary and mitochondrial function in a feline model with features of Heart Failure with Preserved Ejection Fraction