Radiation-induced lipoprotein-associated phospholipase A2 increases lysophosphatidylcholine and induces endothelial cell damage

• Published in: Toxicology (Amsterdam) Vol. 458; p. 152841
• Main Authors: Kim, So-Ra, Heo, Jong-Ik, Park, Jeong-Woo, Kang, Chang-Mo, Kim, Kwang Seok
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 30.06.2021
• Subjects: Endothelial cell damage; Inflammation; Ionizing radiation; Lp-PLA2; Lysophosphatidylcholine; Ionizing radiation; Endothelial cell damage; Inflammation; Lysophosphatidylcholine; Lp-PLA2
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2021.152841

The cardiotoxicity of various anticancer therapies, including radiotherapy, can lead to cardiovascular complications. These complications can range from damaging cardiac tissues within the irradiation field to increasing the long-term risks of developing heart failure, coronary artery disease, and myocardial infarction. We analyzed radiation-induced metabolites capable of mediating critical biological processes, such as inflammation, senescence, and apoptosis. Previously, by applying QTOF-MASS analysis to irradiated human fibroblasts, we identified that metabolite sets of lysophosphatidylcholine (LPC) were increased in these cells. In this study, radiation-induced LPC accumulation in human aortic endothelial cells (HAECs) increased reactive oxygen species (ROS) production and senescence-associated-beta-galactosidase staining, in addition to decreasing their tube-forming ability. Knockdown of lipoprotein-associated phospholipase A2 (Lp-PLA2) with small interfering RNA (siRNA) inhibited the increased LPC production induced by radiation, and reduced the radiation-induced cell damage produced by ROS and oxidized low-density lipoprotein (LDL). Lp-PLA2 depletion abolished the induction of proinflammatory factors, such as interleukin 1β, tumor necrosis factor-alpha, matrix metalloproteinase 2, and matrix metalloproteinase 9, as well as adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and E-selection. Likewise, we showed that Lp-PLA2 expression was upregulated in the vasculature of irradiated rat, resulting in increased LPC production and LDL oxidation. Our data demonstrate that radiation-induced LPC production is a potential risk factor for cardiotoxicity that is mediated by Lp-PLA2 activity, suggesting that LPC and Lp-PLA2 offer potential diagnostic and therapeutic approaches to cardiovascular damage during radiotherapy.