MKP-1 expression and stabilization and cGK Ialpha prevent diabetes- associated abnormalities in VSMC migration.
Diabetes mellitus is a major risk factor in the development of atherosclerosis and cardiovascular disease conditions, involving intimal injury and enhanced vascular smooth muscle cell (VSMC) migration. We report a mechanistic basis for divergences between insulin's inhibitory effects on migration of aortic VSMC from control Wistar Kyoto (WKY) rats versus Goto-Kakizaki (GK) diabetic rats. In normal WKY VSMC, insulin increased MAPK phosphatase-1 (MKP-1) expression as well as MKP-1 phosphorylation, which stabilizes it, and inhibited PDGF-mediated MAPK phosphorylation and cell migration. In contrast, basal migration was elevated in GK diabetic VSMCs, and all of insulin's effects on MKP-1 expression and phosphorylation, MAPK phosphorylation, and PDGF-stimulated migration were markedly inhibited. The critical importance of MKP-1 in insulin inhibition of VSMC migration was evident from several observations. MKP-1 small interfering RNA inhibited MKP-1 expression and abolished insulin inhibition of PDGF-induced VSMC migration. Conversely, adenoviral expression of MKP-1 decreased MAPK phosphorylation and basal migration rate and restored insulin's ability to inhibit PDGF-directed migration in GK diabetic VSMCs. Also, the proteasomal inhibitors lactacystin and MG132 partially restored MKP-1 protein levels in GK diabetic VSMCs and inhibited their migration. Furthermore, GK diabetic aortic VSMCs had reduced cGMP-dependent protein kinase Ialpha (cGK Ialpha) levels as well as insulin-dependent, but not sodium nitroprusside-dependent, stimulation of cGMP. Adenoviral expression of cGK Ialpha enhanced MKP-1 inhibition of MAPK phosphorylation and VSMC migration. We conclude that enhanced VSMC migration in GK diabetic rats is due at least in part to a failure of insulin-stimulated cGMP/cGK Ialpha signaling, MKP-1 expression, and stabilization and thus MAPK inactivation.
Jacob
Asha
A
Diabetes Rsearch Laboratory, Winthrop University Hospital, Mineola 11501, USA.
Smolenski
Albert
A
Lohmann
Suzanne M
SM
Begum
Najma
N
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; C015482:protein kinase modulator; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases