Inhibition of DAPK3 suppresses radiation-induced cellular senescence by activation of a PGC1α-dependent metabolism pathway in brain endothelial cells.
Ji-Eun ParkJeong Woo ParkMyong-Kyu SimSo Ra KimKwang Seok KimPublished in: The journals of gerontology. Series A, Biological sciences and medical sciences (2024)
In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and ROS. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism-associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.
Keyphrases
- drug delivery
- endothelial cells
- dna damage
- radiation induced
- stress induced
- radiation therapy
- high glucose
- cognitive decline
- protein kinase
- vascular endothelial growth factor
- cell proliferation
- skeletal muscle
- resting state
- poor prognosis
- white matter
- mild cognitive impairment
- oxidative stress
- squamous cell carcinoma
- gene expression
- traumatic brain injury
- spinal cord
- cerebral ischemia
- multiple sclerosis
- cell cycle
- genome wide
- risk assessment
- locally advanced