Lovastatin Protects Human Endothelial Cells from Killing by Ionizing Radiation without Impairing Induction and Repair of DNA Double-Strand Breaks

Abstract

3-hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are frequently used lipid-lowering drugs. Moreover, they are reported to exert pleiotropic effects on cellular stress responses, proliferation, and apoptosis. Whether statins affect the sensitivity of primary human cells to ionizing radiation (IR) is still unknown. The present study aims at answering this question. The effect of lovastatin on IR-provoked cytotoxicity was analyzed in primary human umbilical vein endothelial cells (HUVEC). To this end, cell viability, proliferation, and apoptosis as well as DNA damage-related stress responses were investigated. The data show that lovastatin protects HUVEC from IR-induced cell death. Lovastatin did not confer radioresistance to human fibroblasts. The radioprotective, antiapoptotic effect of lovastatin was observed at low, physiologically relevant dose level (1 micromol/L). Lovastatin affected various IR-induced stress responses in HUVEC: It attenuated the increase in p53/p21 protein level and impaired the activation of nuclear factor-kappaB, Chk-1, and Akt kinase but did not inhibit extracellular signal-regulated kinase activation. Exposure of HUVEC to IR did not change the level of Bax and Bcl-2 and did not cause activation of caspase-3, indicating that radioprotection by lovastatin does not depend on the modulation of the mitochondrial death pathway. Also, IR-induced DNA double-strand break formation and repair were not influenced by lovastatin. The data show that lovastatin has multiple inhibitory effects on IR-stimulated DNA damage-dependent stress responses in HUVEC. Because lovastatin causes radioresistance, it might be useful in the clinic for attenuating side effects of radiation therapy that are related to endothelial cell damage.