Endothelial nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome regulation in atherosclerosis.
Cardiovasc Res
; 120(8): 883-898, 2024 Jul 02.
Article
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| MEDLINE
| ID: mdl-38626254
ABSTRACT
AIMS:
The activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in endothelial cells (ECs) contributes to vascular inflammation in atherosclerosis. Considering the high glycolytic rate of ECs, we delineated whether and how glycolysis determines endothelial NLRP3 inflammasome activation in atherosclerosis. METHODS ANDRESULTS:
Our results demonstrated a significant up-regulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key regulator of glycolysis, in human and mouse atherosclerotic endothelium, which positively correlated with NLRP3 levels. Atherosclerotic stimuli up-regulated endothelial PFKFB3 expression via sterol regulatory element-binding protein 2 (SREBP2) transactivation. EC-selective haplodeficiency of Pfkfb3 in Apoe-/- mice resulted in reduced endothelial NLRP3 inflammasome activation and attenuation of atherogenesis. Mechanistic investigations revealed that PFKFB3-driven glycolysis increased the NADH content and induced oligomerization of C-terminal binding protein 1 (CtBP1), an NADH-sensitive transcriptional co-repressor. The monomer form, but not the oligomer form, of CtBP1 was found to associate with the transcriptional repressor Forkhead box P1 (FOXP1) and acted as a transrepressor of inflammasome components, including NLRP3, caspase-1, and interleukin-1ß (IL-1ß). Interfering with NADH-induced CtBP1 oligomerization restored its binding to FOXP1 and inhibited the glycolysis-dependent up-regulation of NLRP3, Caspase-1, and IL-1ß. Additionally, EC-specific overexpression of NADH-insensitive CtBP1 alleviates atherosclerosis.CONCLUSION:
Our findings highlight the existence of a glycolysis-dependent NADH/CtBP/FOXP1-transrepression pathway that regulates endothelial NLRP3 inflammasome activation in atherogenesis. This pathway represents a potential target for selective PFKFB3 inhibitors or strategies aimed at disrupting CtBP1 oligomerization to modulate atherosclerosis.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Fosfofructoquinasa-2
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Células Endoteliales
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Modelos Animales de Enfermedad
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Aterosclerosis
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Inflamasomas
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Proteína con Dominio Pirina 3 de la Familia NLR
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Ratones Noqueados para ApoE
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Glucólisis
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cardiovasc Res
Año:
2024
Tipo del documento:
Article