Cytosolic phospholipase A2 regulates viability of irradiated vascular endothelium

E. M. Yazlovitskaya, A. G. Linkous, D. K. Thotala, K. C. Cuneo, D. E. Hallahan

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Radiosensitivity of various normal tissues is largely dependent on radiation-triggered signal transduction pathways. Radiation simultaneously initiates distinct signaling from both DNA damage and cell membrane. Specifically, DNA strand breaks initiate cell-cycle delay, strand-break repair or programmed cell death, whereas membrane-derived signaling through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) enhances cell viability. Here, activation of cytosolic phospholipase A2 (cPLA2) and production of the lipid second-messenger lysophosphatidylcholine were identified as initial events (within 2min) required for radiation-induced activation of Akt and ERK1/2 in vascular endothelial cells. Inhibition of cPLA2 significantly enhanced radiation-induced cytotoxicity due to an increased number of multinucleated giant cells and cell cycle-independent accumulation of cyclin B1 within 24-48h of irradiation. Delayed programmed cell death was detected at 72-96h after treatment. Endothelial functions were also affected by inhibition of cPLA2 during irradiation resulting in attenuated cell migration and tubule formation. The role of cPLA2 in the regulation of radiation-induced activation of Akt and ERK1/2 and cell viability was confirmed using human umbilical vein endothelial cells transfected with shRNA for cPLA2α and cultured embryonic fibroblasts from cPLA2α-/- mice. In summary, an immediate radiation-induced cPLA2-dependent signaling was identified that regulates cell viability and, therefore, represents one of the key regulators of radioresistance of vascular endothelial cells.

Original languageEnglish
Pages (from-to)1641-1653
Number of pages13
JournalCell Death and Differentiation
Volume15
Issue number10
DOIs
StatePublished - Jul 21 2008
Externally publishedYes

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