Dataset Information

Extracellular Matrix Proteomics of Human Heart Failure

ABSTRACT: MS analysis of human cardiac samples from left ventricles of patients undergoing cardiac transplantation due to ischaemic heart failure (n=5) or non-ischaemic heart failure (n=10), as well as controls samples (n=6). Analysis of extracellular matrix protein enriched extracts.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Heart Failure

SUBMITTER: Javier Barallobre-Barreiro

LAB HEAD: Javier Barallobre-Barreiro

PROVIDER: PXD028908 | Pride | 2021-12-15

REPOSITORIES: Pride

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Publications

Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling.

Barallobre-Barreiro Javier J Radovits Tamás T Fava Marika M Mayr Ursula U Lin Wen-Yu WY Ermolaeva Elizaveta E Martínez-López Diego D Lindberg Eric L EL Duregotti Elisa E Daróczi László L Hasman Maria M Schmidt Lukas E LE Singh Bhawana B Lu Ruifang R Baig Ferheen F Siedlar Aleksandra Malgorzata AM Cuello Friederike F Catibog Norman N Theofilatos Konstantinos K Shah Ajay M AM Crespo-Leiro Maria G MG Doménech Nieves N Hübner Norbert N Merkely Béla B Mayr Manuel M

Circulation 20211122 25

<h4>Background</h4>Remodeling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulfate proteoglycans such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown.<h4>Methods</h4>Versican remodeling was assessed in mice lacking th ...[more]

PMID: 34806902

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Project 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.

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