NFκB (Nuclear Factor κ-Light-Chain Enhancer of Activated B Cells) Activity Regulates Cell-Type-Specific and Context-Specific Susceptibility to Calcification in the Aortic Valve.
Animals
Aortic Valve
/ metabolism
Calcinosis
/ etiology
Cell Differentiation
Cells, Cultured
Cellular Microenvironment
Disease Models, Animal
Endothelial Cells
/ metabolism
Heart Valve Diseases
/ etiology
Humans
Hypercholesterolemia
/ complications
I-kappa B Kinase
/ genetics
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B
/ genetics
NFATC Transcription Factors
/ genetics
Osteogenesis
Receptors, LDL
/ genetics
Signal Transduction
Transcription Factor RelA
/ genetics
aortic valve
endothelial cell
homeostasis
hypercholesterolemia
osteocalcin
Journal
Arteriosclerosis, thrombosis, and vascular biology
ISSN: 1524-4636
Titre abrégé: Arterioscler Thromb Vasc Biol
Pays: United States
ID NLM: 9505803
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
pubmed:
3
1
2020
medline:
15
7
2020
entrez:
3
1
2020
Statut:
ppublish
Résumé
Although often studied independently, little is known about how aortic valve endothelial cells and valve interstitial cells interact collaborate to maintain tissue homeostasis or drive valve calcific pathogenesis. Inflammatory signaling is a recognized initiator of valve calcification, but the cell-type-specific downstream mechanisms have not been elucidated. In this study, we test how inflammatory signaling via NFκB (nuclear factor κ-light-chain enhancer of activated B cells) activity coordinates unique and shared mechanisms of valve endothelial cells and valve interstitial cells differentiation during calcific progression. Approach and Results: Activated NFκB was present throughout the calcific aortic valve disease (CAVD) process in both endothelial and interstitial cell populations in an established mouse model of hypercholesterolemia-induced CAVD and in human CAVD. NFκB activity induces endothelial to mesenchymal transformation in 3-dimensional cultured aortic valve endothelial cells and subsequent osteogenic calcification of transformed cells. Similarly, 3-dimensional cultured valve interstitial cells calcified via NFκB-mediated osteogenic differentiation. NFκB-mediated endothelial to mesenchymal transformation was directly demonstrated in vivo during CAVD via genetic lineage tracking. Genetic deletion of NFκB in either whole valves or valve endothelium only was sufficient to prevent valve-specific molecular and cellular mechanisms of CAVD in vivo despite the persistence of a CAVD inducing environment. Our results identify NFκB signaling as an essential molecular regulator for both valve endothelial and interstitial participation in CAVD pathogenesis. Direct demonstration of valve endothelial cell endothelial to mesenchymal transformation transmigration in vivo during CAVD highlights a new cellular population for further investigation in CAVD morbidity. The efficacy of valve-specific NFκB modulation in inhibiting hypercholesterolemic CAVD suggests potential benefits of multicell type integrated investigation for biological therapeutic development and evaluation for CAVD.
Identifiants
pubmed: 31893948
doi: 10.1161/ATVBAHA.119.313248
pmc: PMC7388286
mid: NIHMS1548917
doi:
Substances chimiques
NF-kappa B
0
NFATC Transcription Factors
0
RELA protein, human
0
Receptors, LDL
0
Rela protein, mouse
0
Transcription Factor RelA
0
I-kappa B Kinase
EC 2.7.11.10
Ikbkb protein, mouse
EC 2.7.11.10
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
638-655Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL111770
Pays : United States
Organisme : NHLBI NIH HHS
ID : R21 HL118672
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143247
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128745
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL078881
Pays : United States
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