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Articles in PresS, published online ahead of print May 8, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00110.2002
Submitted on March 12, 2002
Accepted on April 25, 2002
1 Diabetes Research Laboratory, Winthrop University Hospital, Mineola, NY, USA
2 Division of Molecular Cardiovascular Biology, Childrens Hospital Medical Center, Cincinnati, Ohio, USA
3 Institut fur Klinische Biochemie und Pathobiochemie, Medizinische Universitatsklinik, Wurzburg, Wurzburg, Germany
* To whom correspondence should be addressed. E-mail: nbegum{at}winthrop.org.
In this study, we examined how insulin regulates the intracellular signaling pathways that control VSMC migration in the normal vasculature. Migration of primary cultured VSMCs, measured using a transwell chamber assay was increased in a dose-dependent manner by PDGF. Pretreatment with insulin resulted in a dose-dependent decrease in PDGF-directed VSMC migration. Since mitogen-activated protein kinases (MAPKs) mediate agonist-directed VSMC migration, we examined the effect of insulin on PDGF-stimulated MAPK phosphorylation and activity. PDGF increased MAPK phosphorylation and caused a rapid 8-fold increase in MAPK activity. Pretreatment with insulin resulted in a 60% decrease in PDGF-stimulated MAPK phosphorylation and activation. Insulin inhibition of MAPK was accompanied by a rapid induction of MAPK phosphatase (MKP-1), a dual specificity threonine/tyrosine phosphatase which inactivates MAPKs by dephosphorylation. Pretreatment with L-NMMA and Rp-8-Br-cGMPS, inhibitors of the NO/cGMP pathway, blocked insulin-induced MKP-1 expression, abolished insulin inactivation of MAPK and restored PDGF-stimulated MAPK activation and migration. In contrast, adenoviral infection of VSMCs with MKP-1 or cGMP dependent protein kinase I
(cGK I ), the downstream effector of cGMP signaling, blocked the activation of MAPK and prevented PDGF-directed VSMC migration. Expression of an anti-sense MKP-1 RNA prevented insulin inhibitory effect on MAPK phosphorylation and restored PDGF-direction VSMC migration. We conclude that in normal vasculature, insulin inhibition of VSMC migration may be mediated in part by NO/cGMP/cGK I induction of MKP-1 and consequent inactivation of MAPK.
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