PXD027626

PXD027626 is an original dataset announced via ProteomeXchange.

Title	Extracellular Matrix Protein 1 as a critical mediator of inflammation-to-fibrosis crosstalk in wound healing after myocardial infarction
Description	Aims and introduction: Cardiac fibrosis is the hallmark of cardiac disease, particularly myocardial infarction (MI), and is one of the most prevalent causes of heart failure. MI is intricately linked to inflammation, extracellular matrix (ECM) remodelling, and cardiac fibrosis, however the mechanisms underpinning these events remain poorly understood. We recently identified that ECM1 has potential to play a key role in cardiac wound healing but the cellular origins in the heart and specific mechanisms of ECM1 in fibrosis remain elusive. Therefore, we investigated the spatiotemporal, cell specific, expression profile of ECM1 in the healthy and diseased mouse and human heart and investigate ECM1 dependent human cardiac fibroblast (HuCFb) cell signalling mechanisms. Methods and results: Western blotting, immunohistochemistry (IHC) and mRNA in-situ hybridisation revealed that ECM1 protein expression was significantly upregulated in human ischaemic and dilated heart failure patients, and predominantly localised interstitially to fibrotic, inflammatory, and peri-vascular areas. ECM1 specific analysis of the Litviňuková et al. (2020) single-cell and -nuclei RNA sequencing (sc/snRNAseq) dataset of healthy human hearts, and the Farbehi et al. (2019) scRNAseq dataset of mouse hearts post-MI demonstrated that ECM1 expression originates from fibroblasts, macrophages, and pericytes/vascular mural cells in the heart. Further, we identify that post-MI ECM1 is expressed in a temporal dynamic flux from unactivated fibroblasts in sham-operated mice, to M1 macrophages (M1MΦ) at day-3, and myofibroblasts and M2MΦ at day-7. Phosphoproteomics of ECM1 treated human cardiac fibroblast cells (HuCFb) alongside ECM1 to HuCFb cell surface protein binding pull-down and mass spectrometry, revealed that ECM1 signalling goes via proteins associated with Rho protein signal transduction, cell-cell adhesion, microtubule dynamics, and cell chemotaxis pathways, potentially initiated by ECM1 to CTNND1 binding on the cell surface. Further mechanistic analyses identified that ECM1 inhibits HuCFb cell migration and stimulates inflammatory (IL-6 and IL-1β mRNA expression), fibrotic (TGF-β1, TGF-β2 and Col1a2 mRNA expression), and non-canonical Wnt signalling pathways (Wnt5a mRNA expression and JNK1/2/3 and MYPT1 phosphorylation). Conclusions: This study demonstrates that ECM1 expression originates from macrophages and fibroblasts in the mouse and human heart. ECM1 has significant effects on HuCFb migration, inflammatory, fibrotic, Rho protein, and Wnt5a/non-canonical Wnt signalling pathways. Together, ECM1 plays an important role in cardiac wound healing and may represent a novel mechanism of inflammation-fibrosis crosstalk and progression post-MI.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_07:02:57.421.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Barbara Darnhofer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos; maXis

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-28 04:38:38	ID requested
⏵ 1	2024-01-26 07:02:58	announced

10.1016/j.jacbts.2023.05.010;

Hardy SA, Liesinger L, Patrick R, Poettler M, Rech L, Gindlhuber J, Mabotuwana NS, Ashour D, Stangl V, Bigland M, Murtha LA, Starkey MR, Scherr D, Hansbro PM, Hoefler G, Campos Ramos G, Cochain C, Harvey RP, Birner-Gruenberger R, Boyle AJ, Rainer PP, Extracellular Matrix Protein-1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction. JACC Basic Transl Sci, 8(12):1539-1554(2023) [pubmed]

submitter keyword: ECM1, adult human cardiac fibroblast (HuCFb) cell line, human, cardiac wound healing, extracellular matrix, heart failure (HF)

Ruth Birner-Gruenberger
contact affiliation	Research and Diagnostic Institute of Pathology, Medical University of Graz, Stiftingtalstrasse 6, 8010 Graz, Austria; Faculty of Technical Chemistry, Institute of Chemical Technologies and Analytics, Technische Universität Wien, Getreidemarkt 9/164, 1060 Vienna, Austria
contact email	ruth.birner-gruenberger@tuwien.ac.at
lab head
Barbara Darnhofer
contact affiliation	Omics Center Graz
contact email	barbara.darnhofer@klinikum-graz.at
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD027626

PRIDE project URI

• PRIDE
  1. PXD027626
     1. Label: PRIDE project
     2. Name: Extracellular Matrix Protein 1 as a critical mediator of inflammation-to-fibrosis crosstalk in wound healing after myocardial infarction