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ENHANCED SPHINGOSINE‐1‐PHOSPHATE MEDIATED SMOOTH MUSCLE CELL MIGRATION IN METABOLIC SYNDROME IS REDOX DEPENDENT
Author(s) -
Davies Mark G,
Roztocil Elisa,
Nicholl Suzanne
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a750-d
Subject(s) - chemistry , in vitro , oleic acid , scavenger receptor , cell migration , linoleic acid , sphingosine 1 phosphate , biochemistry , fatty acid , glucose uptake , medicine , endocrinology , receptor , sphingosine , biology , insulin , lipoprotein , cholesterol
BACKGROUND: Metabolic syndrome, an exploding public health concern, results in a high glucose, free fatty acid (FFA)‐rich environment in the bodys tissues. The aim of this study was to examine the mechanisms of S‐1‐P mediated migration of SMC in an in vitro model of metabolic syndrome METHODS: Rat arterial SMCs were cultured in vitro in the presence and absence of high glucose concentrations (40mM) with and without the addition of the FFA, oleic (40μM 18:1) and linoleic acid (40μM 18:2) for 48 hrs prior to testing. Linear wound and Boyden microchemotaxis assays of migration were performed in response to S‐1‐P and western blotting was performed for activation of MEK1/2 and ERK1/2. S‐1‐P induced MMP‐2 activity in the media was determined by gelatin zymography. RESULTS: In the presence of elevated glucose, S‐1‐P mediated migration is enhanced by 2 fold (p<0.05) while the presence of high glucose and a FFA‐rich conditions enhanced S‐1‐P mediated migration four‐fold (p<0.01). Activation of MEK1/2 and ERK1/2 in response to S‐1‐P was increased 5‐fold (p<0.01). MMP‐2 activity in the media was also significantly enhanced. Preincubation with N‐acetyl cysteine, a free radical scavenger blocked both the enhanced migration and signaling responses observed. CONCLUSIONS:In the presence of a high glucose and FFA, activation of ERK1/2 and MMP‐2 is augmented and is associated with enhanced SMC migration. This pathway is redox dependent. Defining the changes in cell biology induced by metabolic syndrome in the vessel wall is key to defining new therapeutic strategies.