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1 The Diabetes Research Laboratory, Winthrop University Hospital, Mineola 11501 and 2 School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794; 3 Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039; and 4 Institut für Klinische Biochemie und Pathobiochemie, Medizinische Universitätsklinik, D97080 Würzburg, Germany
In this study, we examined the role
of insulin in the control of vascular smooth muscle cell (VSMC)
migration in the normal vasculature. Platelet-derived growth factor
(PDGF) increased VSMC migration, which was inhibited by pretreatment
with insulin in a dose-dependent manner. Insulin also caused a 60%
decrease in PDGF-stimulated mitogen-activated protein kinase (MAPK)
phosphorylation and activation. Insulin inhibition of MAPK was
accompanied by a rapid induction of MAPK phosphatase (MKP-1), which
inactivates MAPKs by dephosphorylation. Pretreatment with inhibitors of
the nitric oxide (NO)/cGMP pathway, blocked insulin-induced MKP-1 expression 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 antisense MKP-1 RNA prevented insulin's inhibitory effect and restored PDGF-directed VSMC migration and MAPK
phosphorylation. We conclude that insulin inhibition of VSMC migration
may be mediated in part by NO/cGMP/cGK I induction of MKP-1 and
consequent inactivation of MAPKs.
nitric oxide; guanosine 3',5'-cyclic monophosphate; cGMP-dependent
protein kinase I; platelet-derived growth factor; hypertension
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