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Experiment for Order #1794
Summary Data Summary
Investigator Roth, Rachel
Description 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.

Applicable research area(s): Obesity, Metabolism
Status Completed
Public Release 5/20/2012
Animal Age Measured In: week(s) post-natal (w)
Flags has-data-flagSame StrainExperiment Description
Data Analysis
Experimental Conditions1
Catalog Items4
Curation Info (# flags)2
Phenotype Assays4
Phenotype Measurements44
Histology Images0

Strain NameCommon NameFemalesMalesUnknown
db/db;mkp-1 ko

Experimental Factors
 Categorical Values
Name / AbbreviationDescription

Experimental Factor: Experimental Group

This animal belongs to the control group for the experiment.
This animal belongs to experimental group that is homozygous for gene manipulations.
Experimental Factor (Units)
Experimental Group

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