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Title: Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells

Abstract

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

Citation Formats

Kim, Yong Chan, Song, Seok Bean, Lee, Mi Hee, Kang, Kwang Il, Lee, Hayyoung, Paik, Sang-Gi, Kim, Kyoon Eon, and Kim, Young Sang. Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2005.11.099.
Kim, Yong Chan, Song, Seok Bean, Lee, Mi Hee, Kang, Kwang Il, Lee, Hayyoung, Paik, Sang-Gi, Kim, Kyoon Eon, & Kim, Young Sang. Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells. United States. doi:10.1016/j.bbrc.2005.11.099.
Kim, Yong Chan, Song, Seok Bean, Lee, Mi Hee, Kang, Kwang Il, Lee, Hayyoung, Paik, Sang-Gi, Kim, Kyoon Eon, and Kim, Young Sang. Fri . "Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells". United States. doi:10.1016/j.bbrc.2005.11.099.
@article{osti_20798760,
title = {Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells},
author = {Kim, Yong Chan and Song, Seok Bean and Lee, Mi Hee and Kang, Kwang Il and Lee, Hayyoung and Paik, Sang-Gi and Kim, Kyoon Eon and Kim, Young Sang},
abstractNote = {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.},
doi = {10.1016/j.bbrc.2005.11.099},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 339,
place = {United States},
year = {Fri Jan 20 00:00:00 EST 2006},
month = {Fri Jan 20 00:00:00 EST 2006}
}
  • Highlights: • AMPK-activation induces caspase 3-dependent apoptosis in macrophages. • Apoptosis is associated with decreased mTOR and increased p21 levels. • All effects can be significantly inhibited by the TLR4 agonist lipopolysaccharide. - Abstract: AMP-activated kinase is a cellular energy sensor which is activated in stages of increased ATP consumption. Its activation has been associated with a number of beneficial effects such as decreasing inflammatory processes and the disease progress of diabetes and obesity, respectively. Furthermore, AMPK activation has been linked with induction of cell cycle arrest and apoptosis in cancer and vascular cells, indicating that it might have amore » therapeutic impact for the treatment of cancer and atherosclerosis. However, the impact of AMPK on the proliferation of macrophages, which also play a key role in the formation of atherosclerotic plaques and in inflammatory processes, has not been focused so far. We have assessed the influence of AICAR- and metformin-induced AMPK activation on cell viability of macrophages with and without inflammatory stimulation, respectively. In cells without inflammatory stimulation, we found a strong induction of caspase 3-dependent apoptosis associated with decreased mTOR levels and increased expression of p21. Interestingly, these effects could be inhibited by co-stimulation with bacterial lipopolysaccharide (LPS) but not by other proinflammatory cytokines suggesting that AICAR induces apoptosis via AMPK in a TLR4-pathway dependent manner. In conclusion, our results revealed that AMPK activation is not only associated with positive effects but might also contribute to risk factors by disturbing important features of macrophages. The fact that LPS is able to restore AMPK-associated apoptosis might indicate an important role of TLR4 agonists in preventing unfavorable cell death of immune cells.« less
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