Identification of a functional missense variant in the matrix metallopeptidase 10 (MMP10) gene in two families with premature myocardial infarction.
Humans
Myocardial Infarction
/ genetics
Mutation, Missense
Matrix Metalloproteinase 10
/ genetics
Male
Female
Pedigree
Adult
Molecular Dynamics Simulation
Macrophages
/ metabolism
THP-1 Cells
Middle Aged
Exome Sequencing
Cell Movement
/ genetics
Genetic Predisposition to Disease
Cell Adhesion
/ genetics
Tissue Inhibitor of Metalloproteinase-1
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 May 2024
28 May 2024
Historique:
received:
03
12
2023
accepted:
22
05
2024
medline:
29
5
2024
pubmed:
29
5
2024
entrez:
28
5
2024
Statut:
epublish
Résumé
A positive family history is a major independent risk factor for atherosclerosis, and genetic variation is an important aspect of cardiovascular disease research. We identified a heterozygous missense variant p.L245P in the MMP10 gene in two families with premature myocardial infarction using whole-exome sequencing. The aim of this study was to investigate the consequences of this variant using in-silico and functional in-vitro assays. Molecular dynamics simulations were used to analyze protein interactions, calculate free binding energy, and measure the volume of the substrate-binding cleft of MMP10-TIMP1 models. The p.L245P variant showed an altered protein surface, different intra- and intermolecular interactions of MMP10-TIMP1, a lower total free binding energy between MMP10-TIMP1, and a volume-minimized substrate-binding cleft of MMP10 compared to the wild-type. For the functional assays, human THP-1 cells were transfected with plasmids containing MMP10 cDNA carrying the p.L245P and wild-type variant and differentiated into macrophages. Macrophage adhesion and migration assays were then conducted, and pro-inflammatory chemokine levels were evaluated. The p.L245P variant led to macrophages that were more adherent, less migratory, and secreted higher levels of the pro-inflammatory chemokines CXCL1 and CXCL8 than wild-type macrophages. Thus, the p.L245P variant in MMP10 may influence the pathogenesis of atherosclerosis in families with premature myocardial infarction by altering protein - protein interactions, macrophage adhesion and migration, and expression of pro-inflammatory chemokines, which may increase plaque rupture. These results could contribute to the development of selective MMP10 inhibitors and reduce the risk of atherosclerosis in families with a history of premature myocardial infarction.
Identifiants
pubmed: 38806571
doi: 10.1038/s41598-024-62878-3
pii: 10.1038/s41598-024-62878-3
doi:
Substances chimiques
Matrix Metalloproteinase 10
EC 3.4.24.22
MMP10 protein, human
EC 3.4.24.22
TIMP1 protein, human
0
Tissue Inhibitor of Metalloproteinase-1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
12212Subventions
Organisme : German Research Centre for Cardiovascular Research (DZHK)
ID : FKZ81Z0700107/FKZ81Z0700101/FKZ81Z1700101
Informations de copyright
© 2024. The Author(s).
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