Circulation, Ahead of Print. BACKGROUND:Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms.
This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis.METHODS:Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2.
To assess the role of Dapk2 in vivo, EC-specificDapk2-deficient mice on anApoe-/-background were utilized in carotid artery ligation and Western diet–induced atherosclerosis models. Mice with EC-specific overexpression of Pkm2 harboring either a phospho-refractory mutation (Pkm2T45A) or a phospho-mimicking mutation (Pkm2T45E) were subjected to carotid artery ligation to further elucidate the functional implications of Pkm2 phosphorylation.RESULTS:DAPK2 expression was elevated in OSS-exposed regions of human and murine arteries.
Mechanistically, Krüppel-like factor 2 (KLF2) suppressedDAPK2transcription, whereas OSS-induced KLF2 downregulation led to DAPK2 upregulation.
Circulation published a clinical update in Cardiology on 30 Jan 2026.
The item focuses on DAPK2 Regulates PKM2 Phosphorylation at Threonine 45 to Facilitate Disturbed Flow-Induced Atherosclerosis.
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