Molecular mechanisms of coronary artery disease risk at the PDGFD locus.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 02 2023
15 02 2023
Historique:
received:
03
09
2022
accepted:
03
02
2023
entrez:
15
2
2023
pubmed:
16
2
2023
medline:
18
2
2023
Statut:
epublish
Résumé
Genome wide association studies for coronary artery disease (CAD) have identified a risk locus at 11q22.3. Here, we verify with mechanistic studies that rs2019090 and PDGFD represent the functional variant and gene at this locus. Further, FOXC1/C2 transcription factor binding at rs2019090 is shown to promote PDGFD transcription through the CAD promoting allele. With single cell transcriptomic and histology studies with Pdgfd knockdown in an SMC lineage tracing male atherosclerosis mouse model we find that Pdgfd promotes expansion, migration, and transition of SMC lineage cells to the chondromyocyte phenotype. Pdgfd also increases adventitial fibroblast and pericyte expression of chemokines and leukocyte adhesion molecules, which is linked to plaque macrophage recruitment. Despite these changes there is no effect of Pdgfd deletion on overall plaque burden. These findings suggest that PDGFD mediates CAD risk by promoting deleterious phenotypic changes in SMC, along with an inflammatory response that is primarily focused in the adventitia.
Identifiants
pubmed: 36792607
doi: 10.1038/s41467-023-36518-9
pii: 10.1038/s41467-023-36518-9
pmc: PMC9932166
doi:
Substances chimiques
Pdgfd protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
847Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG011972
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145708
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151535
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL156846
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139478
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134817
Pays : United States
Organisme : NHLBI NIH HHS
ID : L30 HL159413
Pays : United States
Organisme : NHLBI NIH HHS
ID : F32 HL160067
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL153798
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s).
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