Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells.
Macrophages participate in several inflammatory pathologies such as sepsis and arthritis. We examined the effect of simvastatin on the LPS-induced proinflammatory macrophage RAW264.7 cells. Co-treatment of LPS and a non-toxic dose of simvastatin induced cell death in RAW264.7 cells. The cell death was accompanied by disruption of mitochondrial membrane potential (MMP), genomic DNA fragmentation, and caspase-3 activation. Surprisingly, despite caspase-dependent apoptotic cascade being completely blocked by Z-VAD-fmk, a pan-caspase inhibitor, the cell death was only partially repressed. In the presence of Z-VAD-fmk, DNA fragmentation was blocked, but DNA condensation, disruption of MMP, and nuclear translocation of apoptosis inducing factor were obvious. The cell death by simvastatin and LPS was effectively decreased by both the FPP and GGPP treatments as well as mevalonate. Our findings indicate that simvastatin triggers the cell death of LPS-treated RAW264.7 cells through both caspase-dependent and -independent apoptotic pathways, suggesting a novel mechanism of statins for the severe inflammatory disease therapy.
Kim
Yong Chan
YC
Department of Biochemistry, College of Natural Sciences, Chungnam National University, 220 Gung-dong Yuseong-gu, Daejeon 305-764, Republic of Korea.
Song
Seok Bean
SB
Lee
Mi Hee
MH
Kang
Kwang Il
KI
Lee
Hayyoung
H
Paik
Sang-Gi
SG
Kim
Kyoon Eon
KE
Kim
Young Sang
YS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019821:Simvastatin / Q000008:administration & dosage*
D008070:Lipopolysaccharides; D019821:Simvastatin; D020169:Caspases