DAPK2 Regulates Pyruvate Kinase M2 (PKM2) Phosphorylation at Threonine 45 to Facilitate Disturbed Flow-Induced Atherosclerosis
Authors' conclusion
DAPK2-driven phosphorylation of PKM2 at threonine 45 orchestrates endothelial inflammatory responses to disturbed flow, identifying a novel mechanistic axis and potential therapeutic target in atherosclerosis.
Study context
- Population
- Endothelial cells exposed to oscillatory shear stress; human and murine arteries; Apoe-/- mice
Methodological detailsEndothelial cell (EC)-specific Dapk2-deficient Apoe-/- mice, carotid artery ligation and Western diet-induced atherosclerosis models
- EC-specific Dapk2-deficient Apoe-/- mice
- Carotid artery ligation and Western diet-induced atherosclerosis models
Main finding
As reported in the abstract
- DAPK2 expression elevated in oscillatory shear stress (OSS)-exposed regions of human and murine arteries
- KLF2 suppressed DAPK2 transcription; OSS-induced KLF2 downregulation led to DAPK2 upregulation
- EC-specific Dapk2 deficiency or pharmacological inhibition suppressed EC activation and atherogenesis in Apoe-/- mice; reversed by wild-type Dapk2 but not dominant-negative mutant
- DAPK2 bound PKM2 and directly phosphorylated it at threonine 45, leading to PKM2 dimerization and nuclear translocation
- Nuclear PKM2 activated VCAM-1 and ICAM-1 expression via direct interaction with and activation of STAT1
- Elevated PKM2T45 and STAT1Y701 phosphorylation in atheroprone endothelium
- EC-specific Pkm2T45A overexpression mitigated disturbed flow-induced atherogenesis; Pkm2T45E abrogated protection of Dapk2 deficiency
Original publication
DAPK2 Regulates PKM2 Phosphorylation at Threonine 45 to Facilitate Disturbed Flow-Induced Atherosclerosis. Circulation. Published 30 January 2026. doi:10.
Summarised from the published abstract; every number is checked against it