PXD055550-1

PXD055550 is an original dataset announced via ProteomeXchange.

Title	ADAMTS7, a target in atherosclerosis, cooperates with homolog ADAMTS12 to protect against myxomatous valve degeneration
Description	The metalloprotease ADAMTS7, a drug target in atherosclerosis and vascular restenosis, is thought to have no relevant physiological role in the cardiovascular system. However, potential cooperation with its close homolog, ADAMTS12, that may mask such a role remains unexplored. The objective of the present work was to investigate cardiac biology in mice with genetic inactivation of both proteases and to define their proteolytic activities in a relevant matrisome. Here, we demonstrate that these genes are co-expressed in heart valves and buffer the loss of each other by compensatory upregulation. Doppler echocardiography showed that adult Adamts7-/-;Adamts12-/- mice had significant regurgitant aortic valves. Leaflets of Adamts7-/-;Adamts12-/- aortic valves, but not the respective single mutants, were already abnormally shaped at birth and subsequently underwent severe disorganization and enlargement postnatally with calcification near the valve annuli. We further comprehensively identified novel ADAMTS7 and ADAMTS12 substrates relevant to the valve matrisome in secretome libraries from Adamts7-/-;Adamts12-/- cells using the N-terminomics technique Terminal Amine Isotopic Labeling of Substrates (TAILS). Although ADAMTS7 and ADAMTS12 shared several extracellular matrix (ECM) substrates, the cleavage sites and sequence preferences for each protease were distinct. Adamts7-/-;Adamts12-/- valve leaflets showed accumulation of several of the identified ECM substrates tested, including periostin, a matricellular protein crucial for cardiac valve homeostasis. We conclude that the observed myxomatous heart valve degeneration reflects accumulation of diverse ADAMTS7 and ADAMTS12 ECM substrates, as well as perturbation of regulatory pathways with roots in ECM, such as TGFsignaling, which was increased in Adamts7-/-;Adamts12-/- valve leaflets, and propagates ECM dysregulation. These findings are highly relevant to current interest in drugs targeting ADAMTS7 for applications such as mitigation of atherosclerosis or vascular re-stenosis.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_02:41:43.925.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD055550
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Sumit Bhutada
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-04 09:13:38	ID requested
⏵ 1	2025-05-07 02:41:44	announced

10.1016/j.jmccpl.2025.100288;

Mead TJ, Bhutada S, Peruzzi N, Adegboye J, Seifert DE, Cahill E, Drinko J, Donnellan E, Guggiliam A, Popovic Z, Griffin B, Tran-Lundmark K, Apte SS, ADAMTS7, a target in atherosclerosis, cooperates with its homolog ADAMTS12 to protect against myxomatous valve degeneration. J Mol Cell Cardiol Plus, 11():100288(2025) [pubmed]

10.6019/PXD055550;

submitter keyword: metalloproteinase, hypertrophy, chondroitin sulfate, heart valve, fibrosis,ADAMTS, regurgitation, extracellular matrix, myxomatous valve

Suneel Apte
contact affiliation	Lerner Research Institute
contact email	aptes@ccf.org
lab head
Sumit Bhutada
contact affiliation	Cleveland Clinic
contact email	bhutads@ccf.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055550
     1. Label: PRIDE project
     2. Name: ADAMTS7, a target in atherosclerosis, cooperates with homolog ADAMTS12 to protect against myxomatous valve degeneration