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Title: 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.
Authors:
 [1] ;  [2] ;  [1] ;  [2] ;  [2] ;  [3] ;  [1] ;  [4]
  1. Department of Biochemistry, College of Natural Sciences, Chungnam National University, 220 Gung-dong Yuseong-gu, Daejeon 305-764 (Korea, Republic of)
  2. Institute of Biotechnology, Chungnam National University, 220 Gung-dong Yuseong-gu, Daejeon 305-764 (Korea, Republic of)
  3. Department of Biology, Division of Life Science, Chungnam National University, 220 Gung-dong Yuseong-gu, Daejeon 305-764 (Korea, Republic of)
  4. Department of Biochemistry, College of Natural Sciences, Chungnam National University, 220 Gung-dong Yuseong-gu, Daejeon 305-764 (Korea, Republic of). E-mail: young@cnu.ac.kr
Publication Date:
OSTI Identifier:
20798760
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 339; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2005.11.099; PII: S0006-291X(05)02637-9; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; DNA; FRAGMENTATION; INFLAMMATION; MACROPHAGES; PATHOLOGY; RHEUMATIC DISEASES; THERAPY; TRANSLOCATION