PXD022575

PXD022575 is an original dataset announced via ProteomeXchange.

Title	Carnitine O-octanoyltransferase is a novel inducer of vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction
Description	Objective – Vascular calcification is a critical pathology associated with increased cardiovascular event risk, but there are no FDA-approved anti-calcific therapies. We hypothesized and validated that an unbiased screening approach would identify novel mediators of human vascular calcification. Approach and Results – We performed an unbiased quantitative proteomics and pathway network analysis that identified increased carnitine O-octanoyltransferase (CROT) in calcifying primary human coronary artery smooth muscle cells (SMCs). Additionally, human carotid artery atherosclerotic plaques contained increased immunoreactive CROT near calcified regions. CROT siRNA reduced fibrocalcific response in calcifying SMCs. In agreement, histidine 327 to alanine point mutation inactivated human CROT fatty acid metabolism enzymatic activity and suppressed SMC calcification. CROT siRNA restored mitochondrial proteome alterations and suppressed mitochondrial fragmentation in calcifying SMCs. Lipidomics analysis of SMCs incubated with CROT siRNA revealed increased eicosapentaenoic acid, a vascular calcification inhibitor. CRISPR/Cas9-mediated Crot deficiency in low-density lipoprotein receptor-deficient mice reduced aortic and carotid artery calcification without altering bone density, or liver and plasma cholesterol and triglyceride concentrations. Conclusions – CROT is a novel inducer of vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction, as such CROT inhibition has strong potential as an anti-fibrocalcific therapy.
HostingRepository	PRIDE
AnnounceDate	2021-02-26
AnnouncementXML	Submission_2021-02-26_13:12:04.119.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sasha Singh
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2020-11-17 01:53:56	ID requested
⏵ 1	2021-02-26 13:12:05	announced

Okui T, Iwashita M, Rogers MA, Halu A, Atkins SK, Kuraoka S, Abdelhamid I, Higashi H, Ramsaroop A, Aikawa M, Singh SA, Aikawa E, CROT (Carnitine O-Octanoyltransferase) Is a Novel Contributing Factor in Vascular Calcification via Promoting Fatty Acid Metabolism and Mitochondrial Dysfunction. Arterioscler Thromb Vasc Biol, 41(2):755-768(2021) [pubmed]

submitter keyword: CROT, cardiovascular calcification, human primary smooth muscle cells

Elena Aikawa
contact affiliation	Harvard Medical School/Brigham and Women's Hospital
contact email	eaikawa@bwh.harvard.edu
lab head
Sasha Singh
contact affiliation	Brigham and Women's Hospital, Harvard Medical School
contact email	sasingh@bwh.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022575
     1. Label: PRIDE project
     2. Name: Carnitine O-octanoyltransferase is a novel inducer of vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction