PXD026582-1

PXD026582 is an original dataset announced via ProteomeXchange.

Title	The Heart has Intrinsic Ketogenic Capacity that is Facultatively Upregulated in Heart Failure with Preserved Ejection Fraction
Description	Heart Failure with preserved Ejection Fraction or ‘HFpEF’ is now the most common type of heart failure worldwide, with considerable morbidity and mortality, and with no effective pharmacotherapies1. For the first time, we show that the human and murine HFpEF heart have impaired uptake of ketone bodies, and reveal an intrinsic capability of human and murine hearts to generate their own ketones via the canonical rate-limiting ketogenic enzyme, 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2). We demonstrate that protein levels of HMGCS2 are dramatically elevated in HFpEF myocardium that does not overcome reduced specific activity of this enzyme, due to hyperacetylation caused by depletion of the de-acetylating enzyme sirtuin 3 and decreased oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio, upon which the deacetylation activity of sirtuins is dependent. For the first time, we show that the canonical stimuli that serve to turn on ketogenesis in the liver are also present locally in the HFpEF heart, enhanced by a profound energy deficiency as determined by depleted phosphocreatine/ adenosine triphosphate (PCr/ATP) ratio. Thus, metabolically inflexible HFpEF hearts try to auto-regulate their energy supply by upregulating ketogenesis as an apparent “rescue strategy”. These results serve to reframe our understanding of cardiac ketone metabolism and open opportunities for novel therapeutic strategies for HFpEF, which are urgently needed.
HostingRepository	PRIDE
AnnounceDate	2025-05-26
AnnouncementXML	Submission_2025-05-25_16:13:05.943.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Travis Ruan
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-09 01:26:24	ID requested
⏵ 1	2025-05-25 16:13:07	announced

10.1161/circresaha.124.325550;

Koay YC, McIntosh B, Ng YH, Cao Y, Wang XS, Han Y, Tomita S, Bai AY, Hunter B, Misra A, Loughrey CM, Bannon PG, Lal S, Lusis AJ, Kaye DM, Larance M, O'Sullivan JF, Therapy in HFpEF. Circ Res, 136(10):1113-1130(2025) [pubmed]

submitter keyword: Heart, HFpEF, ketones

Mark Larance
contact affiliation	The University of Sydney
contact email	mark.larance@sydney.edu.au
lab head
Travis Ruan
contact affiliation	The University of Sydney
contact email	Travis.Ruan@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026582
     1. Label: PRIDE project
     2. Name: The Heart has Intrinsic Ketogenic Capacity that is Facultatively Upregulated in Heart Failure with Preserved Ejection Fraction