PXD038117

PXD038117 is an original dataset announced via ProteomeXchange.

Title	Sortilin Drives Valvular Interstitial Cells to a Combined Inflammatory Myofibroblast-Osteogenic Phenotype in Calcific Aortic Valve Disease as Revealed by Single-cell Analysis
Description	Background: Calcific aortic valve disease (CAVD), the most common valve disease is comprised of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. Methods: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14 and 21 days; and processed for imaging, proteomics, transcriptomics and single-cell RNA sequencing (scRNA-seq). Results: The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice versus littermate controls. We identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin and p-38 MAPK signaling. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6 and SAA1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. Conclusions: Sortilin promotes experimental CAVD by mediating valvular fibrosis and calcification, and newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in aortic valve calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:19:22.587.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD038117
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Adrien Lupieri
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-11 10:15:43	ID requested
1	2024-01-04 08:33:59	announced
⏵ 2	2024-10-22 06:19:23	announced	2024-10-22: Updated project metadata.

Iqbal F, Schlotter F, Becker-Greene D, Lupieri A, Goettsch C, Hutcheson JD, Rogers MA, Itoh S, Halu A, Lee LH, Blaser MC, Mlynarchik AK, Hagita S, Kuraoka S, Chen HY, Engert JC, Passos LSA, Jha PK, Osborn EA, Jaffer FA, Body SC, Robson SC, Thanassoulis G, Aikawa M, Singh SA, Sonawane AR, Aikawa E, Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity. Eur Heart J, 44(10):885-898(2023) [pubmed]

10.6019/PXD038117;

10.1093/eurheartj/ehac818;

submitter keyword: calcification,aortic stenosis, sortilin, inflammation, single-cell RNA sequencing, fibrosis

Elena Aikawa
contact affiliation	The Center for Excellence in Vascular Biology, Cardiovascular Division The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
contact email	eaikawa@bwh.harvard.edu
lab head
Adrien Lupieri
contact affiliation	Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
contact email	adrien.lupieri@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038117
     1. Label: PRIDE project
     2. Name: Sortilin Drives Valvular Interstitial Cells to a Combined Inflammatory Myofibroblast-Osteogenic Phenotype in Calcific Aortic Valve Disease as Revealed by Single-cell Analysis