TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation
Authors' conclusion
TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.
Study context
- Population
- Aortic tissues of patients and mice with atherosclerosis; senescent vascular smooth muscle cell (VSMC) models; VSMC-specific Trap1 knockout ApoeKO mice
Main finding
As reported in the abstract
- VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming
- TRAP1 significantly increased aerobic glycolysis, elevating lactate production
- Accumulated lactate promoted H4K12la by down-regulating histone delactylase HDAC3
- H4K12la enriched in senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence
- In ApoeKOTrap1SMCKO mice, plaque area, senescence markers, H4K12la and SASP were reduced
- Pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation attenuated atherosclerosis in vivo
Original publication
TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation. Eur Heart J. Published 1 August 2024. doi:10.
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