PMID- 22991462
OWN - NLM
STAT- MEDLINE
DCOM- 20130108
LR  - 20240322
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 41
DP  - 2012 Oct 9
TI  - Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage 
      recruitment.
PG  - E2803-12
LID - 10.1073/pnas.1212596109 [doi]
AB  - Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn 
      are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported 
      that metabolic disorders prime monocytes for enhanced recruitment into vascular 
      lesions by increasing monocytes' responsiveness to chemoattractants. However, the 
      molecular details of this proatherogenic mechanism were not known. Here we show 
      that monocyte priming results in the S-glutathionylation and subsequent 
      inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes 
      to diabetic conditions resulted in the loss of MKP-1 protein levels, the 
      hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 
      (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 
      mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression 
      blunted both MAPK activation and monocyte adhesion and migration induced by 
      MCP-1. Metabolic stress promoted the S-glutathionylation of MKP-1, targeting 
      MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in 
      metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 
      from degradation and normalized monocyte adhesion and chemotaxis in response to 
      MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in 
      MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in 
      atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated 
      with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated 
      atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central 
      redox-sensitive regulator of monocyte adhesion and migration and showed that the 
      loss of MKP-1 activity is a critical step in monocyte priming and the metabolic 
      stress-induced conversion of blood monocytes into a proatherogenic phenotype.
FAU - Kim, Hong Seok
AU  - Kim HS
AD  - Department of Clinical Laboratory Sciences, University of Texas Health Science 
      Center at San Antonio, San Antonio, TX 78229-3904, USA.
FAU - Ullevig, Sarah L
AU  - Ullevig SL
FAU - Zamora, Debora
AU  - Zamora D
FAU - Lee, Chi Fung
AU  - Lee CF
FAU - Asmis, Reto
AU  - Asmis R
LA  - eng
GR  - P30 CA54174/CA/NCI NIH HHS/United States
GR  - R01 HL070963/HL/NHLBI NIH HHS/United States
GR  - P30 CA054174/CA/NCI NIH HHS/United States
GR  - T32 HL007446/HL/NHLBI NIH HHS/United States
GR  - R01 HL115858/HL/NHLBI NIH HHS/United States
GR  - HL-70963/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120918
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Chemokine CCL2)
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (Receptors, LDL)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/blood/genetics/metabolism
MH  - Blotting, Western
MH  - Cell Adhesion
MH  - Cell Line
MH  - Cells, Cultured
MH  - Chemokine CCL2/pharmacology
MH  - *Chemotaxis
MH  - Diabetes Mellitus, Type 2/blood/genetics/metabolism
MH  - Dual Specificity Phosphatase 1/genetics/*metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - Glutathione/metabolism
MH  - Humans
MH  - Lipoproteins, LDL/pharmacology
MH  - Macrophages/cytology/drug effects/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Monocytes/cytology/drug effects/*metabolism
MH  - Oxidation-Reduction/drug effects
MH  - Phosphorylation/drug effects
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - RNA Interference
MH  - Receptors, LDL/genetics/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC3478659
COIS- The authors declare no conflict of interest.
EDAT- 2012/09/20 06:00
MHDA- 2013/01/09 06:00
PMCR- 2013/04/09
CRDT- 2012/09/20 06:00
PHST- 2012/09/20 06:00 [entrez]
PHST- 2012/09/20 06:00 [pubmed]
PHST- 2013/01/09 06:00 [medline]
PHST- 2013/04/09 00:00 [pmc-release]
AID - 1212596109 [pii]
AID - 201212596 [pii]
AID - 10.1073/pnas.1212596109 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):E2803-12. doi: 
      10.1073/pnas.1212596109. Epub 2012 Sep 18.