PXD024581

PXD024581 is an original dataset announced via ProteomeXchange.

Title	Therapeutic inhibition of acid sensing ion channel 1a recovers heart function after ischemia-reperfusion injury
Description	Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0–6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods and Results: We show that acid sensing ion channel 1a (ASIC1a) plays a key role during cardiac ischemia and demonstrate that ASIC1a is a novel therapeutic target to improve the tolerance of cardiac tissue to IRI. Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cerebrovascular ischemic injuries. Using human pluripotent stem cell derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and two models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:31:04.946.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD024581
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Melanie White
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-08 01:05:38	ID requested
1	2022-11-01 07:42:41	announced
⏵ 2	2023-11-14 08:31:06	announced	2023-11-14: Updated project metadata.

10.6019/PXD024581;

Redd MA, Scheuer SE, Saez NJ, Yoshikawa Y, Chiu HS, Gao L, Hicks M, Villanueva JE, Joshi Y, Chow CY, Cuellar-Partida G, Peart JN, See Hoe LE, Chen X, Sun Y, Suen JY, Hatch RJ, Rollo B, Xia D, Alzubaidi MAH, Maljevic S, Quaife-Ryan GA, Hudson JE, Porrello ER, White MY, Cordwell SJ, Fraser JF, Petrou S, Reichelt ME, Thomas WG, King GF, Macdonald PS, Palpant NJ, Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation, 144(12):947-960(2021) [pubmed]

submitter keyword: Heart, venom, mass spectrometry, therapeutic, human induced pluripotent stem cells, ischemia-reperfusion injury

Melanie White
contact affiliation	Charles Perkins Centre, University of Sydney
contact email	melanie.white@sydney.edu.au
lab head
Melanie White
contact affiliation	University of Sydney
contact email	melanie.white@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024581
     1. Label: PRIDE project
     2. Name: Therapeutic inhibition of acid sensing ion channel 1a recovers heart function after ischemia-reperfusion injury