PMID- 23991041
OWN - NLM
STAT- MEDLINE
DCOM- 20140421
LR  - 20221207
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 8
DP  - 2013
TI  - Impact of glutathione peroxidase-1 deficiency on macrophage foam cell formation 
      and proliferation: implications for atherogenesis.
PG  - e72063
LID - 10.1371/journal.pone.0072063 [doi]
LID - e72063
AB  - Clinical and experimental evidence suggests a protective role for the antioxidant 
      enzyme glutathione peroxidase-1 (GPx-1) in the atherogenic process. GPx-1 
      deficiency accelerates atherosclerosis and increases lesion cellularity in 
      ApoE(-/-) mice. However, the distribution of GPx-1 within the atherosclerotic 
      lesion as well as the mechanisms leading to increased macrophage numbers in 
      lesions is still unknown. Accordingly, the aims of the present study were (1) to 
      analyze which cells express GPx-1 within atherosclerotic lesions and (2) to 
      determine whether a lack of GPx-1 affects macrophage foam cell formation and 
      cellular proliferation. Both in situ-hybridization and immunohistochemistry of 
      lesions of the aortic sinus of ApoE(-/-) mice after 12 weeks on a Western type 
      diet revealed that both macrophages and - even though to a less extent - smooth 
      muscle cells contribute to GPx-1 expression within atherosclerotic lesions. In 
      isolated mouse peritoneal macrophages differentiated for 3 days with 
      macrophage-colony-stimulating factor (MCSF), GPx-1 deficiency increased oxidized 
      low density-lipoprotein (oxLDL) induced foam cell formation and led to increased 
      proliferative activity of peritoneal macrophages. The MCSF- and oxLDL-induced 
      proliferation of peritoneal macrophages from GPx-1(-/-)ApoE(-/-) mice was 
      mediated by the p44/42 MAPK (p44/42 mitogen-activated protein kinase), namely 
      ERK1/2 (extracellular-signal regulated kinase 1/2), signaling pathway as 
      demonstrated by ERK1/2 signaling pathways inhibitors, Western blots on cell 
      lysates with primary antibodies against total and phosphorylated ERK1/2, MEK1/2 
      (mitogen-activated protein kinase kinase 1/2), p90RSK (p90 ribosomal s6 kinase), 
      p38 MAPK and SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), 
      and immunohistochemistry of mice atherosclerotic lesions with antibodies against 
      phosphorylated ERK1/2, MEK1/2 and p90RSK. Representative effects of GPx-1 
      deficiency on both macrophage proliferation and MAPK phosphorylation could be 
      abolished by the GPx mimic ebselen. The present study demonstrates that GPx-1 
      deficiency has a significant impact on macrophage foam cell formation and 
      proliferation via the p44/42 MAPK (ERK1/2) pathway encouraging further studies on 
      new therapeutic strategies against atherosclerosis.
FAU - Cheng, Fei
AU  - Cheng F
AD  - Institute of Clinical Chemistry and Laboratory Medicine, University Medical 
      Center, Johannes Gutenberg-University, Mainz, Germany.
FAU - Torzewski, Michael
AU  - Torzewski M
FAU - Degreif, Adriana
AU  - Degreif A
FAU - Rossmann, Heidi
AU  - Rossmann H
FAU - Canisius, Antje
AU  - Canisius A
FAU - Lackner, Karl J
AU  - Lackner KJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130822
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Apolipoproteins E)
RN  - 0 (CD36 Antigens)
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (Scavenger Receptors, Class A)
RN  - 0 (oxidized low density lipoprotein)
RN  - 81627-83-0 (Macrophage Colony-Stimulating Factor)
RN  - EC 1.11.1.9 (Glutathione Peroxidase)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 1.11.1.9 (Glutathione Peroxidase GPX1)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/*deficiency/genetics
MH  - Atherosclerosis/genetics/metabolism
MH  - Blotting, Western
MH  - CD36 Antigens/genetics
MH  - *Cell Proliferation
MH  - Female
MH  - Foam Cells/cytology/drug effects/*metabolism
MH  - Gene Expression/drug effects
MH  - Glutathione Peroxidase/*deficiency/genetics
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Lipoproteins, LDL/pharmacology
MH  - Macrophage Colony-Stimulating Factor/pharmacology
MH  - Macrophages, Peritoneal/cytology/drug effects/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Scavenger Receptors, Class A/genetics
MH  - Glutathione Peroxidase GPX1
PMC - PMC3750037
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/08/31 06:00
MHDA- 2014/04/22 06:00
PMCR- 2013/08/22
CRDT- 2013/08/31 06:00
PHST- 2012/11/26 00:00 [received]
PHST- 2013/07/10 00:00 [accepted]
PHST- 2013/08/31 06:00 [entrez]
PHST- 2013/08/31 06:00 [pubmed]
PHST- 2014/04/22 06:00 [medline]
PHST- 2013/08/22 00:00 [pmc-release]
AID - PONE-D-12-36973 [pii]
AID - 10.1371/journal.pone.0072063 [doi]
PST - epublish
SO  - PLoS One. 2013 Aug 22;8(8):e72063. doi: 10.1371/journal.pone.0072063. eCollection 
      2013.