Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling.
adrenergic beta-agonists
extracellular matrix
heart failure
proteoglycans
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
21 12 2021
21 12 2021
Historique:
pubmed:
23
11
2021
medline:
5
1
2022
entrez:
22
11
2021
Statut:
ppublish
Résumé
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. Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5 Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5 Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart and that versican accumulation is associated with impaired cardiac function. A comprehensive characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.
Sections du résumé
BACKGROUND
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.
METHODS
Versican remodeling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5
RESULTS
Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in patients with ischemic HF. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II infusion. In Adamts5
CONCLUSIONS
Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart and that versican accumulation is associated with impaired cardiac function. A comprehensive characterization of the cardiac ECM in patients with ischemic HF revealed that β-blockers may have a previously unrecognized beneficial effect on cardiac chondroitin sulfate proteoglycan content.
Identifiants
pubmed: 34806902
doi: 10.1161/CIRCULATIONAHA.121.055732
pmc: PMC8687617
doi:
Substances chimiques
Proteoglycans
0
ADAMTS5 Protein
EC 3.4.24.-
ADAMTS5 protein, human
EC 3.4.24.-
Adamts5 protein, mouse
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2021-2034Subventions
Organisme : British Heart Foundation
ID : FS/19/33/34328
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RM/17/3/33381
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1502/3
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/16/14/32397
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/16/3/32406
Pays : United Kingdom
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