Hyperuricemia suppresses lumican, exacerbating adverse remodeling after myocardial infarction by promoting fibroblast phenotype transition.
Cardiac remodeling
Fibroblasts
Hyperuricemia
Lumican
Myocardial infarction
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
received:
14
06
2024
accepted:
19
10
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
Hyperuricemia is independently associated with a poor prognosis in patients with myocardial infarction (MI). Furthermore, MI induces activation of the repair response in local fibroblasts, resulting in extracellular matrix accumulation that generates a stable fibrotic scar in the infarcted area. However, researchers have not determined whether hyperuricemia affects fibroblast activation and its involvement in postinfarction cardiac remodeling. We aimed to trigger hyperuricemia by administering potassium oxonate in a mouse model of MI to evaluate the role of hyperuricemia in MI pathogenesis. Microarray datasets and single-cell sequencing data from gout patients, heart failure patients, and model mice were used to identify the underlying mechanisms responsible for the effect of hyperuricemia on MI progression. A hyperuricemia-related MI mouse model was established. Cardiac function was assessed, followed by sample collection and a uric acid assay. We conducted an enzyme-linked immunosorbent assay, histological detection, immunofluorescence, sequencing data processing, single-cell RNA-seq, and functional enrichment analysis. We then isolated and cultured cardiac fibroblasts and performed Western blotting, quantitative real-time polymerase chain reaction, and shRNA-mediated lumican knockdown assays. Hyperuricemia decreased cardiac function, increased mortality, and aggravated adverse fibrosis remodeling in mice after MI. These outcomes were closely related to reduced levels of fibroblast-derived lumican. This reduction activated the TGF-β/SMAD signaling pathway to induce aberrant myofibroblast activation and extracellular matrix deposition in the infarcted area. Furthermore, lumican supplementation or uric acid-lowering therapy with allopurinol alleviated hyperuricemia-mediated abnormal cardiac remodeling. Hyperuricemia aggravates postinfarction cardiac remodeling by reducing lumican expression and promoting fibroblast phenotype transition. We highlight the clinical importance of lowering uric acid levels in hyperuricemia-related MI to prevent adverse ventricular remodeling.
Sections du résumé
BACKGROUND
BACKGROUND
Hyperuricemia is independently associated with a poor prognosis in patients with myocardial infarction (MI). Furthermore, MI induces activation of the repair response in local fibroblasts, resulting in extracellular matrix accumulation that generates a stable fibrotic scar in the infarcted area. However, researchers have not determined whether hyperuricemia affects fibroblast activation and its involvement in postinfarction cardiac remodeling.
OBJECTIVES
OBJECTIVE
We aimed to trigger hyperuricemia by administering potassium oxonate in a mouse model of MI to evaluate the role of hyperuricemia in MI pathogenesis.
METHODS
METHODS
Microarray datasets and single-cell sequencing data from gout patients, heart failure patients, and model mice were used to identify the underlying mechanisms responsible for the effect of hyperuricemia on MI progression. A hyperuricemia-related MI mouse model was established. Cardiac function was assessed, followed by sample collection and a uric acid assay. We conducted an enzyme-linked immunosorbent assay, histological detection, immunofluorescence, sequencing data processing, single-cell RNA-seq, and functional enrichment analysis. We then isolated and cultured cardiac fibroblasts and performed Western blotting, quantitative real-time polymerase chain reaction, and shRNA-mediated lumican knockdown assays.
RESULTS
RESULTS
Hyperuricemia decreased cardiac function, increased mortality, and aggravated adverse fibrosis remodeling in mice after MI. These outcomes were closely related to reduced levels of fibroblast-derived lumican. This reduction activated the TGF-β/SMAD signaling pathway to induce aberrant myofibroblast activation and extracellular matrix deposition in the infarcted area. Furthermore, lumican supplementation or uric acid-lowering therapy with allopurinol alleviated hyperuricemia-mediated abnormal cardiac remodeling.
CONCLUSION
CONCLUSIONS
Hyperuricemia aggravates postinfarction cardiac remodeling by reducing lumican expression and promoting fibroblast phenotype transition. We highlight the clinical importance of lowering uric acid levels in hyperuricemia-related MI to prevent adverse ventricular remodeling.
Identifiants
pubmed: 39482719
doi: 10.1186/s12967-024-05778-4
pii: 10.1186/s12967-024-05778-4
doi:
Substances chimiques
Lumican
0
Uric Acid
268B43MJ25
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
983Subventions
Organisme : National Natural Science Foundation of China
ID : 82360105
Organisme : National Natural Science Foundation of China
ID : 81960058
Organisme : National Natural Science Foundation of China
ID : 82300292
Organisme : Key Research and Development Program of Jiangxi Province
ID : 20223BBG71010
Organisme : the Natural Science Foundation of Jiangxi Province
ID : 20224BAB206004
Organisme : Postdoctoral Research Foundation of China
ID : 2023TQ0086
Informations de copyright
© 2024. The Author(s).
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