PXD028952

PXD028952 is an original dataset announced via ProteomeXchange.

Title	Migraine-associated mutation in the Na,K-ATPase leads to disturbances in cardiac metabolism and reduced cardiac function
Description	Background. Mutations in ATP1A2 gene encoding the Na,K-ATPase α2 isoform is associated with familial hemiplegic migraine type 2 (FHM2). Migraine with aura is a known risk factor for heart disease. The Na,K-ATPase is important for cardiac function but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results. Mice heterozygous for the FHM2-associated G301R mutation in the Atp1a2 gene (α2+/G301R mice) and matching wild type (WT) controls were compared. Reduced expression of the Na,K-ATPase α2 isoform and increased expression of the α1 isoform was observed in hearts from α2+/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction was shown in hearts from 8-month-old α2+/G301R mice (cardiac magnetic resonance imaging) and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old α2+/G301R mice were similar to WT mice. Amplified Na,K-ATPase-dependent Src/Ras/Erk1/2 signaling was observed in hearts from 8-month-old α2+/G301R mice and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malonedialdehyde measurements), and a heart failure-associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential was similar between the groups (JC-1 dye assay). Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8-month-old α2+/G301R mice. Conclusions. Our findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K-ATPase-dependent ROS signaling through the Src/Ras/Erk1/2 pathway.
HostingRepository	PRIDE
AnnounceDate	2022-05-20
AnnouncementXML	Submission_2022-05-19_22:38:28.583.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hans Christian Beck
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-05 08:09:11	ID requested
⏵ 1	2022-05-19 22:38:29	announced

Staehr C, Rohde PD, Krarup NT, Ringgaard S, Laustsen C, Johnsen J, Nielsen R, Beck HC, Morth JP, Lykke-Hartmann K, Jespersen NR, Abramochkin D, Nyegaard M, B, ø, tker HE, Aalkjaer C, Matchkov V, Migraine-Associated Mutation in the Na,K-ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function. J Am Heart Assoc, 11(7):e021814(2022) [pubmed]

submitter keyword: Oxidant Stress, Cell Signaling, Heart Failure, Contractile Function, Gene Expression and Regulation

Hans Christian Beck
contact affiliation	Centre for Clinical Proteomics, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark
contact email	hans.christian.beck@rsyd.dk
lab head
Hans Christian Beck
contact affiliation	Odense University Hospital, Odense, Denmark
contact email	hans.christian.beck@rsyd.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD028952
     1. Label: PRIDE project
     2. Name: Migraine-associated mutation in the Na,K-ATPase leads to disturbances in cardiac metabolism and reduced cardiac function